Methods and compounds for inhibiting MRP1

ABSTRACT

The present invention further relates to a method of inhibiting MRP1 in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I).

This application is the U.S. National Stage filing of PCT/US00/32443,filed Dec. 11, 2000, which claims the benefit of U.S. ProvisionalApplications Serial Nos. 60/171,373, filed on Dec. 22, 1999; No.60/226,076, filed on Aug. 17, 2000; and No. 60/234,539, filed on Sep.22, 2000.

BACKGROUND

Along with surgery and radiotherapy, chemotherapy continues to be aneffective therapy for many cancers. In fact, several types of cancer,such as Hodgkin's disease, large cell lymphoma, acute lymphocyticleukemia, testicular cancer and early stage breast cancer, are nowconsidered to be curable by chemotherapy. Other cancers such as ovariancancer, small cell lung and advanced breast cancer, while not yetcurable, are exhibiting positive response to combination chemotherapy.

One of the most important unsolved problems in cancer treatment is drugresistance. After selection for resistance to a single cytotoxic drug,cells may become cross resistant to a whole range of drugs withdifferent structures and cellular targets, e.g., alkylating agents,antimetabolites, hormones, platinum-containing drugs, and naturalproducts. This phenomenon is known as multidrug resistance (MDR). Insome types of cells, this resistance is inherent, while in others, suchas small cell lung cancer, it is usually acquired.

Such resistance is known to be multifactorial and is conferred by atleast two proteins: the 170 kDa P-glycoprotein (MDR1) and the morerecently identified 190 kDa multidrug resistance protein (MRP1).Although both MDR1 and MRP1 belong to the ATP-binding cassettesuperfamily of transport proteins, they are structurally very differentmolecules and share less than 15% amino acid homology. Despite thestructural divergence between the two proteins, by 1994 there were noknown consistent differences in the resistance patterns of MDR1 and MRP1cell lines. However, the association, or lack thereof, of MRP1 andresistance to particular oncolytics is known. See Cole, et. al.,“Pharmacological Characterization of Multidrug Resistant MRP-transfectedHuman Tumor Cells”, Cancer Research, 54:5902-5910, 1994. Doxorubicin,daunorubicin, epirubicin, vincristine, paclitaxel, mitoxantrone,melphalan, and etoposide are substrates of MRP1, i.e., MRP1 can bind tothese oncolytics and redistribute them away from their site of action,the nucleus, and out of the cell. Id. and Marquardt, D., and Center, M.S., Cancer Research, 52:3157, 1992.

Doxorubicin, daunorubicin, and epirubicin are members of theanthracycline class of oncolytics. They are isolates of various strainsof Streptomyces and act by inhibiting nucleic acid synthesis. Theseagents are useful in treating neoplasms of the bone, ovaries, bladder,thyroid, and especially the breast. They are also useful in thetreatment of acute lymphoblastic and myeloblastic leukemia, Wilm'stumor, neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin'slymphomas, and bronchogenic carcinoma.

Vincristine, a member of the vinca alkaloid class of oncolytics, is anisolate of a common flowering herb, the periwinkle plant (Vinca roseaLinn). The mechanism of action of vincristine is still underinvestigation but has been related to the inhibition of microtubuleformation in the mitotic spindle. Vincristine is useful in the treatmentof acute leukemia, Hodgkin's disease, non-Hodgkin's malignant lymphomas,rhabdomyosarcoma, neuroblastoma, and Wilm's tumor.

Etoposide, a member of the epipodophyllotoxin class of oncolytics, is asemisynthetic derivative of podophyllotoxin. Etoposide acts as atopoisomerase inhibitor and is useful in the therapy of neoplasms of thetestis, and lung.

It is presently unknown what determines whether a cell line will acquireresistance via a MDR1 or MRP1 mechanism. Due to the tissue specificityof these transporters and/or in the case where one mechanismpredominates or is exclusive, it would be useful to have a selectiveinhibitor of that one over the other. Furthermore, when administering adrug or drugs that are substrates of either protein, it would beparticularly advantageous to coadminister an agent that is a selectiveinhibitor of that protein. It is, therefore, desirable to providecompounds that are selective inhibitors of MDR1 or MRP1.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula:

where:

A is a C₃-C₈ cycloalkyl, optionally substituted 1-3 times with a C₁-C₄alkyl;

het is a five (5) membered heterocyclic ring comprising N and a secondheteroatom selected from N, O, or S;

wherein the non-fused carbon atom of the heteroaryl ring may beoptionally substituted with R^(b): C₁-C₆ alkyl, optionally substitutedaryl, optionally substituted heterocycle, an amino acid ester, CH₂OH,CH₂O-heterocycle, halo, CH₂N₃, CH₂SR¹, CH₂NR⁴R⁶, OR¹, SR¹³,S(CH₂)_(k)-phenyl, or NR⁴R⁶; provided that when het is pyrazole orimidazole, the saturated nitrogen of the het ring may be optionallysubstituted with R^(a): C₁-C₄ alkyl;

k is 0, 1, 2, 3, or 4;

n is 0, 1, or 2;

p is 0 or 1;

q is 0, 1, or 2;

r is 0, 1, or 2;

t is 0, 1, 2, 3, or 4;

u is 0, 1, 2, 3, or 4;

Y is —E—C(O)R³, —E—CH═CHR¹³, —E—C(OH)R¹³, —E—NR⁴R⁵, —E—OR²,—E—S(O)_(q)R¹³, —E—SO₂NR⁴R⁶, —C(R¹¹)═NR⁶, or an optionally substitutedheterocycle;

E is a bond or —C(R¹¹)(R¹¹)—;

R¹ is independently at each occurrence hydrogen or C₁-C₆ alkyl;

R² is independently at each occurrence hydrogen, C₁-C₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl,optionally substituted aryl, or optionally substituted heterocycle,C(O)-aryl, or (CH₂)₂NR⁴R⁵;

R³ is independently at each occurrence hydrogen, C₁-C₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl,optionally substituted aryl, optionally substituted heterocycle, OR¹³,or NR⁴R⁶;

R⁴ is independently at each occurrence hydrogen, C₁-C₆ alkyl, optionallysubstituted (C₁-C₆ alkyl)-aryl, optionally substituted aryl, or R⁴ andR⁵, R⁶, R^(6′) combine to form ═CR¹R¹⁴;

R⁵ is independently at each occurrence hydrogen, C₁-C₆ alkyl, C₁-C₄alkoxy, optionally substituted heterocycle, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-C₁₀ bicycloalkyl; optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, optionallysubstituted (C₁-C₄ alkyl)-heterocycle, C(O)C(O)R¹³, C(O)R⁷, CH₂R⁷,SO₂R⁸, a moiety of the formula

or R⁴ and R⁵, together with the nitrogen to which they are attached,combine to form an optionally substituted N-heterocycle;

R⁶ is independently at each occurrence hydrogen, C₁-C₆ alkyl, C₁-C₄alkoxy, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₆-C₁₀ bicycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl,optionally substituted aryl, optionally substituted (C₁-C₄alkyl)-heterocycle, optionally substituted heterocycle, or R⁴ and R⁶,together with the nitrogen to which they are attached, combine to forman optionally substituted N-heterocycle;

R^(6′) is independently at each occurrence hydrogen, C₁-C₆ alkyl, C₁-C₄alkoxy, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₆-C₁₀ bicycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl,optionally substituted aryl, optionally substituted (C₁-C₄alkyl)-heterocycle, optionally substituted heterocycle, (C₁-C₄alkyl)-OR¹³:

wherein the (C₁-C₄ alkyl) of the (C₁-C₄ alkyl)-OR¹³ may be optionallysubstituted from 1 to 2 times with C₁-C₄ alkyl, optionally substitutedaryl, optionally substituted heterocycle;

or R⁴ and R^(6′), together with the nitrogen to which they are attached,combine to form an optionally substituted N-heterocycle;

R⁷ is independently at each occurrence optionally substituted C₁-C₆alkyl, C₁-C₆ alkoxy, (C₁-C₄ alkoxy)-aryl, (C₁-C₄ alkoxy)-heterocycle,(C₁-C₄ alkoxy)-SiCH₃, optionally substituted (C₃-C₈ cycloalkyl),optionally substituted (C₁-C₄ alkyl)-(C₃-C₈ cycloalkyl), optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl,diphenylmethyl, optionally substituted (C₁-C₄ alkyl)-CO-aryl, optionallysubstituted CO-aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle,optionally substituted CH═CH-heterocycle, optionally substitutedphenoxy, optionally substituted heterocycle, optionally substituted(C₁-C₄ alkyl)-phenoxy, (CH₂)_(t)S(O)_(r)R¹,(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), (CH₂)_(t)C(R¹²)(R⁹)O(R¹⁷),(CH₂)_(t)C(R¹²)(R⁹)S(R¹⁷), or NR⁴R^(6′);

R⁸ is independently at each occurrence optionally substituted C₁-C₆alkyl, optionally substituted aryl, optionally substituted (C₁-C₄alkyl)-aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle, oroptionally substituted heterocycle;

R⁹ is independently at each occurrence hydrogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, optionallysubstituted heterocycle, (CH₂)_(u)-(C₁-C₆ alkoxy), optionallysubstituted (CH₂)_(u)—O—(C3-C8 cycloalkyl), optionally substituted(CH₂)_(u)-(C₁-C₄ alkoxy)-aryl, optionally substituted (CH₂)_(u)—O-aryl,optionally substituted (CH₂)_(u)—O-heterocycle, (C₁-C₄ alkyl)-CO₂-(C₁-C₆alkyl), optionally substituted (C₁-C₄ alkyl)-CO₂-(C₃-C₈ cycloalkyl),optionally substituted (C₁-C₄ alkyl)-CO₂-(C₁-C₄ alkyl)-aryl, optionallysubstituted (C₁-C₄ alkyl)-CO₂-aryl, optionally substituted (C₁-C₄alkyl)-CO₂-heterocycle, or R⁹ and R¹² can combine to form a C₃-C₈cycloalkyl;

R¹⁰ is 0 to 4 substituents from the aryl ring independently at eachoccurrence hydrogen, halo, C(O)R³, cyano, optionally substitutedheterocycle, optionally substituted aryl, C≡C—R¹, C₁-C₄ alkoxy, (C₁-C₄alkyl)-phenyl, NR¹⁹R²⁰, or C₂-C₆ alkenyl;

R¹¹ is independently at each occurrence hydrogen, C₁-C₆ alkyl,optionally substituted heterocycle, optionally substituted (C₁-C₄alkyl)-heterocycle, optionally substituted aryl, or optionallysubstituted (C₁-C₄ alkyl)-aryl;

R¹² is independently at each occurrence hydrogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C3-C8 cycloalkyl, optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, optionallysubstituted (C₁-C₄ alkyl)-heterocycle or optionally substitutedheterocycle;

R¹³ is independently at each occurrence hydrogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl,CO₂CH₂CO₂CH₂CH₃, or optionally substituted heterocycle;

R¹⁴ is independently at each occurrence C₁-C₆ alkyl or optionallysubstituted (C₁-C₄ alkyl)-aryl;

R¹⁵ is independently at each occurrence hydrogen, C₁-C₆ alkyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀bicycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle,optionally substituted heterocycle, C(O)OR¹³, SO₂R⁸, C(O)R¹⁸, or amoiety of the formula

R¹⁶ is independently at each occurrence hydrogen, optionally substitutedC₁-C₆ alkyl, optionally substituted aryl, optionally substitutedheterocycle, SO₂R⁸, or —COR⁸; or R¹⁶ and R¹⁵, together with the nitrogento which they are attached, combine to form an optionally substitutedN-heterocycle;

R¹⁷ is independently at each occurrence hydrogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, COR¹⁸,optionally substituted heterocycle, optionally substituted (C₁-C₄alkyl)-heterocycle, optionally substituted C₁-C₆ alkoxy, optionallysubstituted (C₁-C₄ alkoxy)-aryl, optionally substituted (C₁-C₄alkoxy)-heterocycle, (C₁-C₄ alkyl)-N(R¹)(R¹), or an amino acid ester;

R¹⁸ is independently at each occurrence hydrogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, optionallysubstituted heterocycle, (C₁-C₄ alkyl)-NHCO₂-(C₁-C₄ alkyl), oroptionally substituted (C₁-C₄ alkyl)-heterocycle;

R¹⁹ is independently at each occurrence hydrogen, or optionallysubstituted C₁-C₆ alkyl;

R²⁰ is independently at each occurrence hydrogen, optionally substitutedC₁-C₆ alkyl, CH₂OH, CO—(C₁-C₄ alkyl); or a pharmaceutical salt thereof.

The present invention further relates to a method of inhibiting MRP1 ina mammal which comprises administering to a mammal in need thereof aneffective amount of a compound of formula I.

In another embodiment, the present invention relates to a method ofinhibiting a resistant neoplasm, or a neoplasm susceptible to resistancein a mammal which comprises administering to a mammal in need thereof aneffective amount of a compound of formula I in combination with aneffective amount of an oncolytic agent.

The present invention also relates to a pharmaceutical formulationcomprising a compound of formula I in combination with one or moreoncolytics, pharmaceutical carriers, diluents, or excipients therefor.

DETAILED DESCRIPTION OF THE INVENTION

The current invention concerns the discovery that compounds of formula Iare selective inhibitors of multidrug resistant protein (MRP1), and arethus useful in treating MRP1 conferred multidrug resistance (MDR) in aresistant neoplasm and a neoplasm susceptible to resistance.

The terms “inhibit” as it relates to MRP1 and “inhibiting MRP1” refer toprohibiting, alleviating, ameliorating, halting, restraining, slowing orreversing the progression of, or reducing MRP1′s ability to redistributean oncolytic away from the oncolytic's site of action, most often theneoplasm's nucleus, and out of the cell. Additionally, these terms referto (repeat to redistribute) an MRP1 substrate away from the substrate'ssite of action.

As used herein, the term “effective amount of a compound of formula I”refers to an amount of a compound of the present invention which iscapable of inhibiting MRP1. The term “effective amount of an oncolyticagent” refers to an amount of oncolytic agent capable of inhibiting aneoplasm, resistant or otherwise.

The term “inhibiting a resistant neoplasm, or a neoplasm susceptible toresistance” refers to prohibiting, halting, restraining, slowing orreversing the progression of, reducing the growth of, or killingresistant neoplasms and/or neoplasms susceptible to resistance.

The term “resistant neoplasm” refers to a neoplasm, which is resistantto chemotherapy where that resistance is conferred in part, or in total,by MRP1. Such neoplasms include, but are not limited to, neoplasms ofthe bladder, bone, breast, lung(small-cell), testis, and thyroid andalso includes more particular types of cancer such as, but not limitedto, acute lymphoblastic and myeloblastic leukemia, Wilm's tumor,neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin'slymphomas, and bronchogenic carcinoma.

A neoplasm, which is “susceptible to resistance”, is a neoplasm whereresistance is not inherent nor currently present but can be conferred byMRP1 after chemotherapy begins. Thus, the methods of this inventionencompass a prophylactic and therapeutic administration of a compound offormula I.

The term “chemotherapy” refers to the use of one or more oncolyticagents where at least one oncolytic agent is a substrate of MRP1. A“substrate of MRP1” is an oncolytic that binds to MRP1 and isredistributed away from the oncolytic's site of action (the nucleus ofthe neoplasm) and out of the cell, thus, rendering the therapy lesseffective. Preferred oncolytic agents are camptosar, vinorelbine,mitoxantrone, doxorubicin, daunorubicin, epirubicin, vincristine, andetopsoside.

The terms “treat” or “treating” bear their usual meaning which includespreventing, prohibiting, alleviating, ameliorating, halting,restraining, slowing or reversing the progression, or reducing theseverity of MRP1 derived drug resistance in a multidrug resistant tumor.

In the general formulae of the present document, the general chemicalterms have their usual meanings. For example, the term “C₁-C₄ alkyl”refers to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl,cyclobutyl, s-butyl, and t-butyl. The term “C₁-C₆ alkyl” refers to amonovalent, straight, branched, or cyclic saturated hydrocarboncontaining from 1 to 6 carbon atoms. Additionally, the term “C₁-C₆alkyl” includes C₁-C₄ alkyl groups and C₃-C₆ cycloalkyls. The term“C₁-C₆ alkyl” includes, but is not limited to, cyclopentyl, pentyl,hexyl, cyclohexyl, and the like.

The term “C₃-C₈ cycloalkyl” refers to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term “C₅-C₇cycloalkyl” refers to cyclopentyl, cyclohexyl, and cycloheptyl.

The term “C₆-C₁₀ bicycloalkyl” refers to bicyclo-[2.1.1]hexanyl,[2.2.1]heptanyl, [3.2.1]octanyl, [2.2.2]octanyl, [3.2.2]nonanyl,[3.3.1]nonanyl, [3.3.2]decanyl, and [4.3.1]decanyl ring systems; andbenzofused ring systems including 1,2,3,4-tetrahydronaphthalene, indane,1,2-dihydrocyclobuta[1,2-a]benzene, and hydrocyclopropa[1,2-a]benzene.

The terms “optionally substituted C₁-C₄ alkyl” and “optionallysubstituted C₁-C₆ alkyl” refers to a C₁-C₄ alkyl or C₁-C₆ alkyl,respectively, unsubstituted or substituted from 1 to 3 times with halo,C₁-C₄ alkanol, NH₂, or hydroxy.

The terms “C₁-C₄ alkoxy” and “C₁-C₆ alkoxy” refer to moieties of theformula O—(C₁-C₄ alkyl) and O—(C₁-C₆ alkyl) respectively.

The term “optionally substituted C₃-C₈ cycloalkyl” refers to a C₃-C₈cycloalkyl unsubstituted or substituted once with a phenyl, substitutedphenyl, hydroxy, or CO₂R¹ group.

The terms “optionally substituted (C₁-C₄ alkyl)-(C₃-C₈ cycloalkyl)”refers to optionally substituted C₃-C₈ cycloalkyl linked through anoptionally substituted C₁-C₄ alkyl.

The term “optionally substituted O—(C₃-C₈ cycloalkyl)” refers to anoptionally substituted C₃-C₈ cycloalkyl linked through an oxygen atom.

The term “optionally substituted C₆-C₁₀ bicycloalkyl” refers to a C₆-C₁₀bicycloalkyl unsubstituted or substituted once with a phenyl,substituted phenyl, or CO₂R¹ group.

The term “halo” or “halide” refers to fluoro, chloro, bromo, and iodo.

The term “aryl” refers to phenyl, and naphthyl.

The term “optionally substituted aryl” refers to a phenyl and naphthylgroup, respectively, unsubstituted or substituted from 1 to 5 timesindependently with C₁-C₆ alkyl, C₁-C₄ alkoxy, halo, hydroxy,trifluoromethyl, phenyl, phenoxy, SO₂R¹, OR¹¹; NR⁴R⁵, SO₂N(R¹³)₂, NH-Pg,C₁-C₆ alkoxy, benzyloxy, C(O)R¹³, C₅-C₇ cycloalkyl, trifluoromethoxy,SR¹, cyano, or nitro.

The term “optionally substituted (C₁-C₄ alkyl)-aryl” refers tooptionally substituted aryl linked through an optionally substitutedC₁-C₄ alkyl.

The term “optionally substituted O-aryl” refers to an optionallysubstituted aryl linked through an oxygen atom.

The term “optionally substituted phenoxy” refers to a phenoxy groupunsubstituted or substituted from 1 to 3 times independently with C₁-C₆alkyl, halo, hydroxy, trifluoromethyl, NR⁴R⁶, SO₂N(R¹³)₂, NH-Pg, C₁-C₆alkoxy, benzyloxy, C(O)R¹³, C₅-C₇ cycloalkyl, trifluoromethoxy, cyano,or nitro.

The term “optionally substituted (C₁-C₄ alkyl)-phenoxy” refers tounsubstituted or substituted phenoxy linked through an optionallysubstituted C₁-C₄ alkyl.

The term “heterocycle” is taken to mean stable unsaturated and saturated3 to 6 membered rings containing from 1 to 4 heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur, said rings beingoptionally benzofused. All of these rings may be substituted with up tothree substituents independently selected from the group consisting ofhalo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyano, nitro, hydroxy, —S(O)m-(C₁-C₄alkyl) and —S(O)_(m)-phenyl where m is 0, 1 or 2. Saturated ringsinclude, for example, pyrrolidinyl, azetidine, piperidinyl, piperazinyl,tetrahydrofuryl, oxazolidinyl, morpholino, dioxanyl, pyranyl, and thelike. Benzofused saturated rings include indolinyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl and thelike. Unsaturated rings include furyl, thienyl, pyridinyl, pyrrolyl,N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl,thiophenyl, pyridazinyl, and the like. Benzofused unsaturated ringsinclude isoquinolinyl, benzoxazolyl, benzthiazolyl; quinolinyl,benzofuranyl, thionaphthyl, furanopyridine, cinnolinyl,thiophenopyridine, indolyl and the like.

The term “heteroaryl” is taken to mean an unsaturated or benzofusedunsaturated heterocycle as defined in the previous paragraph.

The term “optionally substituted heterocycle” refers to a heterocyclicring unsubstituted or substituted 1 or 3 times independently with aC₁-C₆ alkyl, halo, benzyl, optionally substituted phenyl, SR¹, C₁-C₄alkoxy, CO₂R¹, nitro, cyano, (C₁-C₄ alkyl)-cyano, heterocycle, NR¹⁹R²⁰,COR¹², C₁-C₆ alkanol, benzyloxy, phenoxy, trifluoromethyl. Heterocyclicrings may be additionally substituted 1 or 2 times with an oxo group.

The term “optionally substituted O-heterocycle” refers to an optionallysubstituted heterocycle linked through an oxygen atom.

The term “optionally substituted (C₁-C₄ alkyl)-heterocycle” refers tooptionally substituted heterocycle linked through an optionallysubstituted C₁-C₄ alkyl.

The term “N-heterocycle” refers to a nitrogen containing heterocyclelinked through a nitrogen atom.

The term “optionally substituted N-heterocycle” refers to aN-heterocycle, optionally substituted 1 or 3 times independently with aC₁-C₆ alkyl, halo, benzyl, optionally substituted phenyl, SR¹, C₁-C₄alkoxy, CO₂R¹, nitro, cyano, (C₁-C₄ alkyl)-cyano, heterocycle, NR¹⁹R²⁰,COR¹², C₁-C₆ alkanol, benzyloxy, phenoxy, trifluoromethyl; andadditionally substituted 1 or 2 times with an oxo group.

The term “amino acid ester” as used in this specification refers to anamino acid, where the carboxy group is substituted with a C₁-C₆ alkyl orbenzyl group. That is, the alkyl group when taken together with thecarboxy group forms a C₁-C₆ alkyl ester. A skilled artisan wouldappreciate that some amino acids have two carboxy groups that may besubstituted with a C₁-C₆ alkyl group, for example, aspartic acid andglutamic acid. This invention contemplates the possibility of amino acidmono- or diesters in these circumstances.

The term “amino acid” refers to a chemical unit made up of both a basicamino group and an acidic carboxyl group. Examples of amino acidsinclude alanine, asparagine, cysteine, glutamine, glycine, isoleucine,leucine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine, valine, aspartic acid, glutaric acid, arginine,histidine, and lysine.

The term “protecting group” (Pg) refers to an amino protecting group ora hydroxy protecting group. The species of protecting group will beevident from whether the “Pg” group is attached to a nitrogen atom(amino protecting group) or attached to an oxygen atom (hydroxyprotecting group).

The term “amino protecting group” as used in this specification refersto a substituent(s) of the amino group commonly employed to block orprotect the amino functionality while reacting other functional groupson the compound. Examples of such amino-protecting groups include theformyl group, the trityl group, the phthalimido group, the acetyl group,the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetylgroups, urethane-type blocking groups such as benzyloxycarbonyl,9-fluorenylmethoxycarbonyl (“FMOC”), and the like; and like aminoprotecting groups. The species of amino protecting group employed is notcritical so long as the derivitized amino group is stable to thecondition of subsequent reaction(s) on other positions of the moleculeand can be removed at the appropriate point without disrupting theremainder of the molecule. Similar amino protecting groups used in thecephalosporin, penicillin, and peptide arts are also embraced by theabove terms. Further examples of groups referred to by the above termsare described by T. W. Greene, “Protective Groups in Organic Synthesis”,John Wiley and Sons, New York, N.Y., 1991, Chapter 7 hereafter referredto as “Greene”. A preferred amino protecting group ist-butyloxycarbonyl.

The term “hydroxy protecting group” denotes a group understood by oneskilled in the organic chemical arts of the type described in Chapter 2of Greene. Representative hydroxy protecting groups include, forexample, ether groups including methyl and substituted methyl ethergroups such as methyl ether, methoxymethyl ether, methylthiomethylether, tert-buylthiomethyl ether, (phenyldimethylsilyl)methoxy-methylether, benzyloxymethyl ether, p-methoxybenzyloxy-methyl ether, andtert-butoxymethyl ether; substituted ethyl ether groups such asethoxyethyl ether, 1-(2-chloroethoxy)-ethyl ether,2,2,2-trichloroethoxymethyl ether, and 2-(trimethylsilyl)ethyl ether;isopropyl ether groups; phenyl and substituted phenyl ether groups suchas phenyl ether, p-chlorophenyl ether, p-methoxyphenyl ether, and2,4-dinitrophenyl ether; benzyl and substituted benzyl ether groups suchas benzyl ether, p-methoxybenzyl ether, o-nitrobenzyl ether, and2,6-dichlorobenzyl ether; and alkylsilyl ether groups such astrimethyl-triethyl- and triisopropylsilyl ethers, mixed alkylsilyl ethergroups such as dimethylisopropylsilyl ether, and diethylisopropylsilylether; and ester protecting groups such as formate ester, benzylformateester, mono-, di-, and trichloroacetate esters, phenoxyacetate ester,and p-chlorophenoxyacetate and the like. The species of hydroxyprotecting group employed is not critical so long as the derivatizedhydroxy group is stable to the conditions of subsequent reaction(s) onother positions of the intermediate molecule and can be selectivelyremoved at the appropriate point without disrupting the remainder of themolecule including any other hydroxy protecting group(s).

The term “carbonyl activating group” refers to a substituent of acarbonyl that increases the susceptibility of that carbonyl tonucleophilic addition. Such groups include, but are not limited to,alkoxy, aryloxy, nitrogen containing unsaturated heterocycles, or aminogroups such as oxybenzotriazole, imidazolyl, nitrophenoxy,pentachloro-phenoxy, N-oxysuccinimide, N,N′-dicyclohexylisoure-O-yl,N-hydroxy-N-methoxyamino, and the like; acetates, formates, sulfonatessuch as methanesulfonate, ethanesulfonate, benzenesulfonate, orp-toluenylsulfonate, and the like; and halides especially chloride,bromide, or iodide.

The term “carbonyl activating reagent” refers to a reagent that convertsthe carbonyl of a carboxylic acid group to one that is more prone tonucleophilic addition and includes, but is not limited to, such reagentsas those found in “The Peptides”, Gross and Meienhofer, Eds., AcademicPress (1979), Ch. 2 and M. Bodanszky, “Principles of Peptide Synthesis”,2^(nd) Ed., Springer-Verlag Berlin Heidelberg, 1993, hereafter referredto as “The Peptides” and “Peptide Synthesis” respectively. Specifically,carbonyl activating reagents include thionyl bromide, thionyl chloride,oxalyl chloride, and the like; alcohols such as nitrophenol,pentachlorophenol, and the like; amines such as N-hydroxy-N-methoxyamineand the like; acid halides such as acetic, formic, methanesulfonic,ethanesulfonic, benzenesulfonic, or p-tolylsulfonic acid halide, and thelike; and compounds such as 1,1′-carbonyldiimidazole, benzotriazole,imidazole, N-hydroxysuccinimide, dicyclohexylcarbodiimide, and the like.

In general, the term “pharmaceutical” when used as an adjective meanssubstantially non-toxic to living organisms. For example, the term“pharmaceutical salt” as used herein, refers to salts of the compoundsof formula I which are substantially non-toxic to living organisms. See,e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D.C., “PharmaceuticalSalts”, J. Pharm. Sci., 66:1, 1977. Typical pharmaceutical salts includethose salts prepared by reaction of the compounds of formula I with aninorganic or organic acid or base. Such salts are known as acid additionor base addition salts respectively. These pharmaceutical saltsfrequently have enhanced solubility characteristics compared to thecompound from which they are derived, and thus are often more amenableto formulation as liquids or emulsions.

The term “acid addition salt” refers to a salt of a compound of formulaI prepared by reaction of a compound of formula I with a mineral ororganic acid. For exemplification of pharmaceutical acid addition saltssee, e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D.C., J. Pharm.Sci., 66:1, 1977. Since compounds of this invention can be basic innature, they accordingly react with any of a number of inorganic andorganic acids to form pharmaceutical acid addition salts.

The pharmaceutical acid addition salts of the invention are typicallyformed by reacting the compound of formula I with an equimolar or excessamount of acid. The reactants are generally combined in a mutual solventsuch as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol,benzene, and the like. The salts normally precipitate out of solutionwithin about one hour to about ten days and can be isolated byfiltration or other conventional methods.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids, such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesulfonate, 1,5-naphthalene-disulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and thelike.

The term “base addition salt” refers to a salt of a compound of formulaI prepared by reaction of a compound of formula I with a mineral ororganic base. For exemplification of pharmaceutical base addition saltssee, e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D.C., J. Pharm.Sci., 66:1, 1977. This invention also contemplates pharmaceutical baseaddition salts of compounds of formula I. The skilled artisan wouldappreciate that some compounds of formula I may be acidic in nature andaccordingly react with any of a number of inorganic and organic bases toform pharmaceutical base addition salts. Examples of pharmaceutical baseaddition salts are the ammonium, lithium, potassium, sodium, calcium,magnesium, methylamino, diethylamino, ethylene diamino, cyclohexylamino,and ethanolamino salts, and the like of a compound of formula I.

While all of the compounds of the present invention are useful, certainof the compounds are particularly interesting and are preferred. Thefollowing listing sets out several groups of preferred compounds. Itwill be understood that each of the listings may be combined with otherlistings to create additional groups of preferred embodiments.

i. A is C₅-C₆ cycloalkyl;

ii. A is cyclopentyl;

iii. A is cyclohexyl;

iv. R^(b) is C₁-C₆ alkyl;

v. R^(b) is methyl;

vi. R^(b) is halo;

vii. n is 0:

viii. n is 1;

ix. p is 0;

x. p is 1;

xi. Y is —E—C(O)R³, —E—NR⁴R⁵, or an optionally substituted heterocycle;

xii. Y is —E—C(O)R³;

xiii. Y is —E—NR⁴R⁵;

xiv. Y is an optionally substituted heterocycle;

xv. E is a bond;

xvi. When Y is —E—C(O)R³, R³ is OR¹³, or NR⁴R⁶;

xvii. When Y is —E—C(O)R³, R³ is OR¹³, R¹³ is optionally substitutedC₁-C₆ alkyl;

xviii. When Y is —E—C(O)R³, R³ is OR¹³, R¹³ is methyl;

xix. When Y is —E—C(O)R³, R³ is OR¹³, R¹³ is optionally substituted(C₁-C₄ alkyl)-aryl;

xx. When Y is —E—C(O)R³, R³ is OR¹³ and R¹³ is benzyl;

xxi. When Y is —E—C(O)R³, R³ is OR¹³ and R¹³ is optionally substitutedaryl;

xxii. When Y is —E—C(O)R³, R³ is OR¹³ and R¹³ is phenyl;

xxiii. When Y is —E—C(O)R³, R³ is NR⁴R⁶ and R4 is hydrogen;

xxiv. When Y is —E—C(O)R³, R³ is NR⁴R⁶, R4 is hydrogen, and R⁶ is C₁-C₆alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substitutedC₆-C₁₀ bicycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl,optionally substituted aryl, optionally substituted (C₁-C₄alkyl)-heterocycle, or optionally substituted heterocycle;

xxv. When Y is —E—C(O)R³, R³ is NR⁴R⁶, R⁴ and R⁶, together with thenitrogen to which they are attached, combine to form an optionallysubstituted N-heterocycle;

xxvi. When Y is —E—NR⁴R⁵, R⁴ is hydrogen;

xxvii. When Y is —E—NR⁴R⁵, R⁴ is hydrogen, and R⁵ is C(O)R⁷;

xxviii. When Y is —E—NR⁴R⁵, R⁴ is hydrogen, and R⁵ is C(O)R⁷, R⁷ isC₁-C₆ alkoxy, optionally substituted (C₃-C₈ cycloalkyl), optionallysubstituted (C₁-C₄ alkyl)-(C₃-C₈ cycloalkyl), optionally substituted(C₁-C₄ alkyl)-aryl, optionally substituted aryl, diphenylmethyl,optionally substituted (C₁-C₄ alkyl)-CO-aryl, optionally substitutedCO-aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle, optionallysubstituted heterocycle, (CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), or(CH₂)_(t)C(R¹²)(R⁹)O(R¹⁷);

xxix. When Y is —E—NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, and R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵);

xxx. When Y is —E—NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), R¹² is hydrogen, and R⁹ is phenyl;

xxxi. When Y is —E—NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), R¹² is hydrogen, R⁹ is phenyl, and R16is hydrogen, then R¹⁵ is hydrogen, C₁-C₆ alkyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀ bicycloalkyl, optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, optionallysubstituted (C₁-C₄ alkyl)-heterocycle, optionally substitutedheterocycle, C(O)OR¹³, SO₂R⁸, or C(O)R¹⁸;

xxxii. When Y is —E—NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), R¹² is hydrogen, R⁹ is phenyl, and R16is hydrogen, then R15 is optionally substituted phenyl;

xxxiii. When Y is —E—NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), R¹² is hydrogen, R⁹ is phenyl, and R16is hydrogen, then R15 is optionally substituted heterocycle

xxxiv. When Y is —E—NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), R¹² is hydrogen, and R⁹ is phenyl, thenR¹⁶ and R¹⁵, together with the nitrogen to which they are attached,combine to form an optionally substituted N-heterocycle; .

xxxv. When Y is —E—NR⁴R⁵, R⁴ and R⁵, together with the nitrogen to whichthey are attached, combine to form an optionally substitutedN-heterocycle;

xxxvi. R⁴ is hydrogen

xxxvii. R⁴ is C₁-C₆ alkyl;

xxxviii. R⁵ is hydrogen;

xxxix. R⁵ is optionally substituted heterocycle;

xl. R⁵ is optionally substituted C₆-C₁₀ bicycloalkyl;

xli. R⁵ is optionally substituted (C₁-C₄ alkyl)-aryl;

xlii. R⁵ is SO₂R⁸;

xliii. R⁵ is a moiety of the formula

xliv. R⁶ is hydrogen;

xlv. R⁶ is C₁-C₆ alkyl;

xlvi. R⁶ is optionally substituted C₃-C₈ cycloalkyl;

xlvii. R⁶ is optionally substituted C₆-C₁₀ bicycloalkyl;

xlviii. R⁶ is optionally substituted (C₁-C₄ alkyl)-aryl;

xlix. R⁶ is optionally substituted aryl;

l. R⁶ is optionally substituted (C₁-C₄ alkyl)-heterocycle;

li. R⁶ is optionally substituted heterocycle;

lii. R^(6′) is C₁-C₆ alkyl;

liii. R^(6′) is optionally substituted C₃-C₈ cycloalkyl;

liv. R^(6′) is optionally substituted C₆-C₁₀ bicycloalkyl;

lv. R^(6′) is optionally substituted (C₁-C₄ alkyl)-aryl;

lvi. R^(6′) is optionally substituted aryl;

lvii. R⁷ is optionally substituted C₁-C₆ alkyl;

lviii. R⁷ is C₁-C₆ alkoxy;

lix. R⁷ is (C₁-C₄ alkoxy)-aryl;

lx. R⁷ is optionally substituted (C₃-C₈ cycloalkyl);

lxi. R⁷ is optionally substituted (C₁-C₄ alkyl)-(C₃-C₈ cycloalkyl);

lxii. R⁷ is optionally substituted (C₁-C₄ alkyl)-aryl;

lxiii. R⁷ is optionally substituted aryl;

lxiv. R⁷ is diphenylmethyl;

lxv. R⁷ is optionally substituted (C₁-C₄ alkyl)-CO-aryl;

lxvi. R⁷ is optionally substituted CO-aryl;

lxvii. R⁷ is optionally substituted (C₁-C₄ alkyl)-heterocycle;

lxviii. R⁷ is optionally substituted phenoxy;

lxix. R⁷ is optionally substituted heterocycle;

lxx. R⁷ is (CH₂)_(t)S(O)_(r)R¹;

lxxi. R⁷ is (CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵);

lxxii. R⁷ is (CH₂)_(t)C(R¹²)(R⁹)O(R¹⁷);

lxxiii. R⁷ is (CH₂)_(t)C(R¹²)(R⁹)S(R¹⁷);

lxxiv. R⁷ is NR⁴R^(6′);

lxxv. R⁸ is optionally substituted C₁-C₆ alkyl;

lxxvi. R⁸ is optionally substituted aryl;

lxxvii. R⁸ is optionally substituted (C₁-C₄ alkyl)-aryl;

lxxviii. R⁹ is hydrogen;

lxxix. R⁹ is optionally substituted C₁-C₆ alkyl;

lxxx. R⁹ is optionally substituted C₃-C₈ cycloalkyl;

lxxxi. R⁹ is optionally substituted aryl;

lxxxii. R⁹ is optionally substituted heterocycle;

lxxxiii. R⁹ is optionally substituted (CH₂)_(u)-(C₁-C₄ alkoxy)-aryl;

lxxxiv. R9 and R¹² combine to form a C₃-C₈ cycloalkyl;

lxxxv. R¹⁰ is 1 to 4 substituents selected from the group consisting ofhydrogen, halo, cyano, optionally substituted heterocycle, or NR¹⁹R²⁰;

lxxxvi. R¹⁰ is monosubstituted with chloro;

lxxxvii. R¹⁰ is monosubstituted with cyano;

lxxxviii. R¹⁰ is monosubstituted with NH₂;

lxxxix. R¹¹ is hydrogen;

xc. R¹² is hydrogen;

xci. R¹² is optionally substituted C₁-C₆ alkyl;

xcii. R¹² is optionally substituted aryl;

xciii. R¹³ is hydrogen;

xciv. R¹³ is optionally substituted C₁-C₆ alkyl;

xcv. R¹³ is optionally substituted (C₁-C₄ alkyl)-aryl;

xcvi. R¹³ is optionally substituted aryl;

xcvii. R¹³ is CO₂CH₂CO₂CH₂CH₃;

xcviii. R¹⁵ is hydrogen;

xcix. R¹⁵ is C₁-C₆;

c. R¹⁵ is optionally substituted C₆-C¹⁰ bicycloalkyl;

ci. R¹⁵ is optionally substituted aryl;

cii. R¹⁵ is optionally substituted heterocycle;

ciii. R¹⁵ is C(O)OR¹³;

civ. R¹⁵ is SO₂R⁸;

cv. R¹⁵ is C(O)R¹⁸;

cvi. R¹⁶ is hydrogen;

cvii. R¹⁶ is optionally substituted C₁-C₆ alkyl;

cviii. R¹⁶ and R¹⁵, together with the nitrogen to which they areattached, combine to form an optionally substituted N-heterocycle;

cix. R¹⁷ is hydrogen;

cx. R¹⁷ is optionally substituted C₁-C₆ alkyl,

cxi. R¹⁷ is optionally substituted aryl;

cxii. R¹⁷ is optionally substituted heterocycle;

cxiii. R¹⁸ is hydrogen;

cxiv. R¹⁸ is optionally substituted C₁-C₆ alkyl;

cxv. R¹⁸ is optionally substituted aryl;

cxvi. R¹⁸ is optionally substituted heterocycle;

cxvii. R¹⁸ is (C₁-C₄ alkyl)-NHCO₂—(C₁-C₄ alkyl);

cxviii. R¹⁹ is hydrogen;

cxix. R¹⁹ is optionally substituted C₁-C₆ alkyl;

cxx. R²⁰ is hydrogen;

cxxi. R²⁰ is optionally substituted C₁-C₆ alkyl;

cxxii. R²⁰ is CH₂OH;

cxxiii. R²⁰ is CO—(C₁-C₄ alkyl);

cxxxi. R^(b) is chloro;

cxxxii. R^(a) is hydrogen;

cxxxiii. R^(a) is t-butyl;

cxxxiv. The compound is a pharmaceutical salt; and

cxxxv. The compound is the hydrochloride salt.

The following group, including the racemic trans and cis, and theisolated enantiomers, is illustrative of compounds contemplated withinthe scope of this invention:

a)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-hydroxy-acetamide

b)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-hydroxy-3-methyl-butyramide

c)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-3-hydroxy-3-phenyl-propionamide

d)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-3-hydroxy-3-phenyl-propionamide

e)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-hydroxy-3-methyl-butyramide

f) 1-Hydroxy-cyclopropanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide

g){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-methyl}-methyl-carbamicacid tert-butyl ester

h)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-methylamino-acetamidehydrochloride

i)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-dimethylamino-acetamide

j){1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

k)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-methyl-propionamidehydrochloride

l){[3-(9-Chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-methyl}-carbamic acid tert-butyl ester

m)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-acetamidehydrochloride

n) 2-Hydroxy-hexanoic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide

o)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-hydroxy-benzamide

p)4-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methyl}-piperazine-1-carboxylicacid tert-butyl ester

q)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-phenyl-2-piperazin-1-yl-acetamidedihydrochloride

r){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methyl}-methyl-carbamicacid tert-butyl ester

s)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-methylamino-2-phenyl-acetamidehydrochloride

t)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-2-phenyl-acetamide

u)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-phenyl-2-(4-pyridin-2-yl-piperazin-1-yl)-acetamide

v)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-piperidin-1-yl-acetamide

w)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(4-methyl-piperazin-1-yl)-acetamide

x)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-diethylamino-acetarmide

y)2-Chloro-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-6-methoxy-isonicotinamide

z)3-(9-Chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexanecarboxylicacid (2-hydroxy-1-phenyl-ethyl)-amide

aa)3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexanecarboxylicacid (2-hydroxy-1-phenyl-ethyl)-amide

bb)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazoto[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(methyl-phenyl-amino)-acetamide

cc)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-phenyl-2-(pyridin-3-yloxy)-acetamide

dd)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2(pyridin-3-yloxy)-acetamide

ee){1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-cyclohexyl}-carbamicacid tert-butyl ester.

ff) 1-Amino-cyclohexanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amidehydrochloride

gg)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-morpholin-4-yl-acetamide

hh)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(4-hydroxy-piperidin-1-yl)-acetamide

ii)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-2-yloxy)-acetamide

jj)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-4-yloxy)-acetamide

kk)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-4-ylsulfanyl)-acetamide

ll){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-cyclohexyl-methyl}-carbamicacid tert-butyl ester

mm)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-cyclohexyl-acetamidehydrochloride

nn)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-cyclohexyl-acetamidehydrochloride

oo){[3-(9-Chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-cyclohexyl-methyl}-carbamicacid tert-butyl ester

pp) thieno[3,2-b]pyridine-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide

qq)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(2-chloro-pyridin-4-yloxy)-acetamide

rr)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(quinolin-3-yloxy)-acetamide

ss)2-tert-Butylamino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-acetamide

tt)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-2-ylsulfanyl)-acetamide

uu)(2-aminoindan-2-yl)-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]carboxamide

vv)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-dimethylamino-2-cyclohexylpropionamide

ww)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-dimethylamino-2-(3-chlorophenyl)-propionamide

xx)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-dimethylamino-2-pyrid-1-yl-propionamide

yy)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-dimethylamino-2-fur-3-yl-propionanide

zz)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(2-chlorophenyl)amino-2-(3-chlorophenyl)-propionamnide

aaa)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-diphenylamino-2-phenylpropionarnide

bbb)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclobutyl]-2-hydroxy-acetamide

ccc)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-hydroxy-3-methyl-butyramide

ddd)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cycloheptyl]-3-hydroxy-3-phenyl-propionamide

eee)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclobutyl]-3-hydroxy-3-phenyl-propionamide

fff)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-hydroxy-3-methyl-butyramide

ggg) 1-Hydroxy-cyclopropanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cycloheptyl]-amide

hhh){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-methyl}-methyl-carbamic acid tert-butyl ester

iii)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-methylamino-acetamidehydrochloride

jjj)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-dimethylamino-acetamide

kkk){1-[3-(9-Chloro-3-methyl-4-oxo-H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

lll)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-methyl-propionamidehydrochloride

mmm){[3-(9-Chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-methyl}-carbamicacid tert-butyl ester

nnn)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-acetamidehydrochloride

ooo) 2-Hydroxy-hexanoic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-amide

ppp)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-hydroxy-benzamide

qqq)4-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-phenyl-methyl}-piperazine-1-carboxylicacid tert-butyl ester

rrr)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-phenyl-2-piperazin-1-yl-acetamidedihydrochloride

sss){[3(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-phenyl-methyl}-methyl-carbamicacid tert-butyl ester

ttt)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-methylamino-2-phenyl-acetamidehydrochloride

uuu)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-2-phenyl-acetamide

vvv)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-phenyl-2-(4-pyridin-2-yl-piperazin-1-yl)-acetamide

www)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-piperidin-1-yl-acetamide

xxx)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(4-methyl-piperazin-1-yl)-acetamide

yyy)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-diethylamino-acetamide

zzz)2-Chloro-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylmethyl]-6-methoxy-isonicotinamide

aaaa)3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexanecarboxylicacid (2-hydroxy-1-phenyl-ethyl)-amide

bbbb)3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexanecarboxylicacid (2-hydroxy-1-phenyl-ethyl)-amide

cccc)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(methyl-phenyl-amino)-acetamide

dddd)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-phenyl-2-(pyridin-3-yloxy)-acetamide

eeee)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(pyridin-3-yloxy)-acetamide

ffff){1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-cyclopentyl}-carbamicacid tert-butyl ester.

gggg) 1-Amino-cyclohexanecarboxylic acid[3-(9-chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-amidehydrochloride

hhhh)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-morpholin-4-yl-acetamide

iiii)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(4-hydroxy-piperidin-1-yl)-acetamide

jjjj)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(pyridin-2-yloxy)-acetamide

kkkk)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(pyridin-4-yloxy)-acetamide

llll)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(pyridin-4-ylsulfanyl)-acetamide

mmmm){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-cyclohexyl-methyl}-carbamicacid tert-butyl ester

nnnn)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-cyclohexyl-acetamidehydrochloride

oooo)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-cyclopentyl-acetamidehydrochloride

pppp){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-cyclohexyl-methyl}-carbamicacid tert-butyl ester

qqqq) thieno[3,2-b]pyridine-2-carboxylicacid[3-(9-chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-amide

rrrr)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(2-chloro-pyridin-4-yloxy)-acetamide

ssss)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(quinolin-3-yloxy)-acetamide

tttt)2-tert-Butylmino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-acetamide

uuuu)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(pyridin-2-ylsulfanyl)-acetamide

vvvv)(2-aminoindan-2-yl)-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclopentyl]carboxamide

wwww)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-dimethylamino-2-cyclohexylpropionamide

xxxx)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-dimethylamino-2-(3-chlorophenyl)-propionamide

yyyy)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-dimethylamino-2-pyrid-1-yl-propionamide

zzzz)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-dimethylamino-2-fur-3-yl-propionamide

aaaaa)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(2-chlorophenyl)amino-2-(3-chlorophenyl)-propionamide

bbbbb)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-diphenylamino-2-phenylpropionamide

The compounds of the present invention can be prepared by a variety ofprocedures, some of which are illustrated in the Schemes below. Theparticular order of steps required to produce the compounds of formula Iis dependent upon the particular compound being synthesized, thestarting compound, and the relative lability of the substitutedmoieties.

Compounds of formula I(a), wherein R^(b), the substituent attached tothe non-fused carbon, is C₁-C₆ alkyl, optionally substituted aryl,optionally substituted heterocycle, CH₂OH, or CH₂O-heterocycle may beprepared from compounds of formula II(a) as illustrated in Scheme 1below where Y, A, R¹⁰, het, n, and p are as described supra.

Compounds of formula I(a) may be prepared by dissolving or suspending acompound of formula II(a) in a suitable solvent, preferablydimethylformamide, and adding a suitable base, including potassiummethoxide, potassium tert-butoxide, potassium carbonate, sodiumhexamethyldisilazane, and preferably potassium hexamethyldisilazane. Thebase is typically employed in a one to one ratio. However, as theskilled artisan would appreciate, a slight molar excess, usually inabout a 1.1 to about a 3 fold molar excess relative to the compound offormula II(a), is acceptable.

The reactants are typically combined at a temperature from about 0° C.to about 100° C. When het is isoxazole, oxazole, or imidazole, thereactants are preferably combined at room temperature and the resultingsolution is typically mixed for from about 5 minutes to about 18 hours,preferably from about 15 minutes to about 3 hours. When het is pyrazolethe reactants are preferably combined at room temperature and theresulting solution is typically heated to about 100° C. for about 30minutes to about 18 hours.

It is preferred, when A is cyclopentyl and the base employed ispotassium hexamethyldisilazane, to combine the reactants from about 60°C. to about 100° C. for about 3 to about 6 minutes.

Any protecting groups remaining in the cyclized compound of formula Imay be removed as taught in Greene to provide additional compounds offormula I. Preferred choices of protecting groups and methods for theirremoval may be found in the Preparations and Examples sections below.

Compounds of formula I(b), wherein het is substituted with halo may beprepared from compounds of formula II(b) as illustrated in Scheme 2below where Y, A, R¹⁰, het, n, and p are as described supra.

Compounds of formula I(b) may be prepared by dissolving or suspending acompound of formula II(b) in a suitable solvent and adding a suitablebase, in an inert atmosphere, preferably under N₂. Typically a preferredand convenient solvent is dimethylformamide. A preferred base is sodiumtrimethylsilanolate. The base is typically employed in a slight molarexcess, usually in about a 1.05 fold molar excess relative to thecompound of formula II(b). The reactants are typically combined dropwiseat room temperature over a period of time from about 2 hours to about 4hours.

The skilled artisan would appreciate that if other bases are used in thereaction of Scheme 2, the substituent of the het functionality maychange. For example if sodium methylthiolate is used as the preferredbase, the compound of formula II(b) will be converted into the compoundof formula I wherein the bet functionality is substituted with —SCH₃.

Additionally, the compound of formula I(b) can be prepared according toScheme 1 wherein the reactants are combined at about 0° C. and mixed atabout −10° C. for approximately three hours. The solution is then warmedto room temperature and mixed for an additional 2 to 3 hours.

Certain compounds of formula I(c) are useful MRP1 inhibitors and arealso useful intermediates for the preparation of other compounds offormula I. As is shown in Scheme 3, when R^(b) is CH₂O-Pg, a derivativeof formula I(c) wherein Pg is a protecting group, the compound offormula I(c) may be further reacted by methods known in the art toproduce compounds of formula I(d) where R^(b′) is CH₂OH, CH₂N₃, CH₂SR¹,or CH₂NR⁴R⁶, and Y, A, het, p, n, R¹, R⁴, R⁶, and R¹⁰ are as describedsupra.

Compounds of formula I(d) wherein het is substituted with CH₂OH may beprepared by dissolving or suspending a compound of formula I(c) in asuitable solvent and adding a suitable acid. Typically a preferred andconvenient solvent is methanol/dichloromethane (2:1). A preferred acidis p-toluenesulfonic acid hydrate. The acid is typically employed in aslight molar excess, usually in about a 1.05 fold molar. excess relativeto the compound of formula I(c). The reactants are typically combined atroom temperature and mixed from about 1 hour to about 3 hours.

The skilled artisan would appreciate that the alcohol can be furtherconverted to compounds of formula I(d) where het is substituted withCH₂N₃, CH₂SR¹³, or CH₂NR⁴R⁶ by methods well known in the art. Forgeneral examples of these procedures, see the Preparations and Examplesection.

Compounds of formula I(e) when het is substituted with chloro are usefulMRP1 inhibitors and are also useful intermediates for the preparation ofother compounds of formula I. As is shown in Scheme 4, the compound offormula I(e) may be further reacted with a nucleophile by methods knownin the art to produce compounds of formula I(q) where het is substitutedwith an amino acid ester, OR¹, SR¹³, S(CH₂)_(k)-phenyl, NR⁴R⁶, or anoptionally substituted heterocycle attached via a heteroatom, and Y, A,p, n, k, het, R¹, R⁴, R⁶, R¹⁰, and R¹³ are as described supra.

Compounds of formula I(q) may be prepared by dissolving or suspending acompound of formula I(e) in a suitable solvent and adding an appropriatenucleophile, in an inert atmosphere, preferably under N₂. Typically apreferred and convenient solvent is dimethylformamide. The nucleophileis typically employed in a molar excess, usually in about a 2 to about a4 fold molar excess relative to the compound of formula I(e).

The reactants are preferably combined at room temperature and theresulting solution is typically mixed for about 30 minutes to about 3hours, until the reaction is complete as measured by the consumption ofthe substrate. The skilled artisan would appreciate that the reaction,depending on the nucleophile used, may require more time to react andmay, also require heating. In these instances, it is preferred to mixthe reactants for approximately 15 to approximately 20 hours, then heatthe solution from about 50° C. to about 80° C. and mix for an additional3 hours or until the reaction is complete as measured by the consumptionof the compound of formula I(e).

Compounds of formula I(p) where Y is C(R^(11′))(R¹¹)NR⁴R⁵ may beprepared from compounds of formula I(n) as illustrated in Scheme 5 belowwhere R³ and R¹¹ are equivalent, R^(11′) is H, and het, n, p, A, R⁴, R⁵,and R¹⁰ are as described supra.

The compounds of formula I(n) may be reductively aminated to form thecompounds of formula I(p). Reductive aminations are well knowntransformations, see, e.g., Larock, “Comprehensive OrganicTransformations”, pg. 421, VCH Publishers, New York, N.Y., 1989,hereafter referred to as “Larock”.

Amines of formula III may be dissolved or suspended in a suitablesolvent, preferably methanol, optionally in the presence of a suitablebase, preferably N-methyl morpholine or triethylamine. When the compoundof formula III is an acid addition salt, it is preferred to convert thesalt to its free amine form. A compound of formula I(n) is then added tothe mixture. Optionally, a Lewis acid catalyst, such as titanium(W)isopropoxide, may be employed. Once the compound of formula I(n) hasbeen substantially consumed, the intermediate is typically reacted insitu with a suitable reducing agent to provide the compounds of formulaI(p). The overall conversion may be performed at about 0° C. to theboiling point of the mixture, but room temperature is a preferredreaction temperature. The formation of the compounds of formula I(p) maytake from 15 minutes to 24 hours as measure by the consumption of thesubstrate.

Suitable reducing agents include, but are not limited to, hydrogen overpalladium or platinum on carbon, borane or complexes of borane, e.g.,borane-pyridine, borane-t-butylamine, and borane-dimethylamine complex;and borohydride reducing agents such as sodium borohydride or sodiumcyanoborohydride. Sodium cyanoborohydride is a preferred reducing agent.

Compounds of formula I(r) may be prepared from compounds of formula I(n)as illustrated below where p, n, R³, R⁷, and R¹⁰ are as described supra.

The compounds of formula I(n) may be converted to compounds of formulaI(r). Such reactions are well known transformations, see, e.g., Larock,“Comprehensive Organic Transformations”, pg. 421, VCH Publishers, NewYork, N.Y., 1989, hereafter referred to as “Larock”.

The compound of formula I(n) may be may be reduced to the correspondingalcohol, activated (i.e. mesylation), reacted with an appropriate azide,reduced, and then acylated. Additionally, the Curtius rearrangement maybe employed to give the compound of formula I(r). See thepreparation/Example section for specifics.

The Curtius rearrangement is performed by converting the activatedcompound, in an appropriate solvent, with an appropriate azide, then anappropriate alcohol, to provide a compound of formula I(r). As theskilled artisan would appreciate, the activated compound, dissolved inan appropriate solvent, is first treated with an appropriate azide andoptionally a catalyst to provide the intermediate. The intermediate istreated with an appropriate alcohol to obtain the compound of formulaI(r). Once the reaction is complete, as measured by the consumption ofthe substrate, the resulting compound of formula I(r) may be isolated bystandard extractions and filtrations. If desired, the resulting compoundof formula I(r) may be further purified by chromatography orcrystallization as appropriate.

Appropriate solvents must be capable of dissolving a sufficient amountof the activated compound and the azide for the reaction to proceed.Useful organic solvents include hexamethylphosphoramide,dimethylformamide, and preferably toluene.

The skilled artisan would appreciate that the Curtius rearrangement maybe preformed via a number of azides and that reaction conditions mayvary depending upon the azide used. For example if sodium azide,potassium azide, and the like are used the compound must first beconverted to the activated acid with an appropriate activating agent,such as ethyl chloroformate or sulfuric acid. The substrate may need tobe pretreated with the activating agent, such as the case with ethylchloroformate, or may need to be added simultaneously. The skilledartisan would appreciate the potential for reaction at an ester site ofthe substrate, if the molecule is treated with the azide first as is thecase in these circumstances.

Preferably, diphenylphosphoryl azide is used in the process of thepresent invention without an activating agent.

Appropriate alcohols are lower alkyl alcohols such as methanol, ethanol,propanol, isopropanol, butanol, benzyl, t-butanol, TMS-ethanol, and thelike.

The reaction may be carried out over a large range of concentrations,from about 0.001 molar to about 2.0 molar of the azide, dependent uponthe solubility of the particular azide in the chosen solvent. Thereaction may also be performed on slurries of the azide so long as asufficient amount of the azide is soluble in the solvent for thereaction to proceed. Preferably the process is performed at aconcentration from about 0.1 molar to about 1.0 molar. A concentrationof about 0.3 to about 0.4 molar is most preferred.

Reactions may be performed between about 80° C. and about 130° C.,preferably between about 100° C. and about 120° C. Most preferably thereactants are combined at temperature of about 20° C. to about 30° C.,then heated to about 80° C and about 120° C., the azide is then added,and the reactants are stirred for about 0.5 to about 1.5 hours atreflux. An appropriate alcohol is then added and heated to about 70° C.to about 90° C. for about 3 to about 24 hours, preferably from about 75°C. to about 85° C. for about 8 to about 12 hours.

Compounds of formula I where Y is C(R¹¹)(R¹¹)NR⁴R⁵ or OR², R² is(CH₂)₂NR⁴R⁵, and R⁵ is C₁-C₆ alkyl, optionally substituted (C₁-C₄alkyl)-aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle, or COR⁷,may be prepared from compounds of formula I(f) and I(h) as illustratedin Scheme 6 below where X is halide and het, n, p, R¹¹, R⁴, R¹⁰, and R¹²are as described supra.

The compounds of formulas I(f) and I(h) may be reductively alkylated toform the corresponding compounds of formulas I(g) and I(i),respectively. Reductive alkylation of primary amines are well knowntransformations, see, e.g., Larock, pg. 434-435.

Once it is determined that the compound of formula IV has beensubstantially consumed, the intermediate is typically reacted in situwith a suitable reducing agent to provide the compounds of formula I(g)and I(i), respectively. The overall conversion may be performed at about0° C. to the boiling point of the mixture but room temperature is apreferred reaction temperature. The formation of the compounds offormulas I(g) and I(i) may take from 15 minutes to 24 hours as measuredby the consumption of the substrate.

A base is typically employed when the compound of formula I(f) or I(h)is an acid addition salt in order to convert the salt to its free amineform. Preferred bases for this purpose are N-methylmorpholine andtriethylamine. A preferred Lewis acid catalyst is titanium(IV)isopropoxide. Suitable reducing agents include, but are not limited to,borane or complexes of borane, e.g., borane-pyridine,borane-t-butylamine, and borane-dimethylamine complex; and lithiumaluminum hydride.

Compounds of formulas I(f) and I(h) may be converted to other compoundsof the invention by methods well known in the chemical arts. Additionalcompounds of formula I may be prepared as follows, where Y is —E—NR⁴R⁵or —E—OR², R² is (CH₂)₂NR⁴R⁵, R⁵ is COR⁷, and R⁷ is NR⁴R^(6′) or R⁵ is amoiety of the formula

R³⁰ is R^(6′) or R⁸; and het, n, p, A, R⁴, R^(6′), R⁸, R¹⁰, and R¹¹ areas described supra.

The primary amines of formulas I(h) and I(f) may be reacted, by methodswell known in the art, with the isocyanates or isothiocyantes of formulaVII to prepare the corresponding ureas and thioureas of formulas I(k)and I(o), see, generally, March, pages 802-803.

Compounds of formula I where Y is C(R¹¹)(R¹¹)NR⁴R⁵, and R⁵ is SO₂R⁸ canbe prepared as described in Scheme 8, wherein het, n, p, A, R¹¹, R⁴, R⁸,and R¹⁰ are as described supra.

Compounds of formula I(f) may be converted to other compounds of theinvention via standard combinatorial synthetic techniques. For example,a compound of formula I(f) dissolved or suspended in a suitable solvent,optionally in the presence of a base, may be treated with a compound offormula VI to provide a compound of formula I(j) where R⁵ is SO₂R⁸.Typically a preferred and convenient solvent is dichloromethane. When abase is employed, triethylamine is typically preferred. Furthermore,when a base is employed, the base and compound of formula VI aretypically employed in a slight stoichiometric excess. For example a 1.01to 1.40 molar excess, relative to the compound of formula I(f), isgenerally employed. About 1.15 to about 1.25 fold molar excess istypically preferred. When a base is not employed, the compound offormula VI is typically employed in a relatively larger stoichiometricexcess. For example, about a 1.5 to about a 3 molar excess, relative tothe compound of formula I(f), is usually employed. About 1.8 to about2.2 fold molar excess is typically preferred. The reaction is usuallyperformed at a temperature range of about 0° C. to about the refluxtemperature of the solvent for from 10 minutes to 18 hours. Preferably,the reaction is performed at about 15° C. to about 40° C. for from 5minutes to about 1 hour.

Compounds of formula I where Y is C(O)R³ and R³ is OR¹³ or NR⁴R⁶ may beprepared from compounds of formula I(l) as illustrated in Scheme 9 belowwherein R³¹ is NR⁴R⁶ or OR¹³; and het, n, p, A, R⁴, R⁶, and R¹³ are asdescribed supra.

Compounds of formula I(l), prepared as described in Scheme 1, may alsobe converted to other compounds of the invention via solution or solidphase synthetic techniques. For example, acids of formula I(l) may betreated with activating agents to form the activated carboxylic acidderivatives of formula I(l) by methods well known in the chemical arts.See, e.g., The Peptides, Peptide Synthesis and the Examples andPreparations sections below.

Generally, preparation of compounds of formula 1(m) where R³¹ is NR⁴R⁶is performed in a manner similar to the reaction of compounds of formulaI(f) or I(h) described in Scheme 6. Specifically, such compounds offormula I(m) may be prepared by dissolving or suspending a compound ofthe activated carboxylic acid derivatives of formula I(l) in a suitablesolvent, optionally in the presence of a suitable base, and adding anamine of formula m. Typically a preferred and convenient solvent isdichloromethane. Preferred bases are triethylamine andpiperidinylmethylpolystyrene resin. The amine is typically employed in amolar excess. For example, about a 1.5 to about a 3 molar excess,relative to the compound of the activated carboxylic acid derivatives offormula I(l) is usually employed. About 1.8 to about 2.2 fold molarexcess is typically preferred. The reaction is usually performed in atemperature range of about 0° C. to about the reflux temperature of thesolvent for from 10 minutes to 18 hours. Preferably, the reaction isperformed at about 15° C. to about 40° C. for from 5 minutes to about2.5 hours.

The compounds of formula I(m) where R³¹ is OR¹³ may be prepared bymethods well known in the chemical arts. For instruction on theconversion of activated carboxylic acid derivatives to esters see, e.g.,Larock at 978-979. Alternatively, these compounds of formula I(m) may beprepared directly from the acids of formula I(l) as taught in the Larockreference at pages 966-972.

The starting materials and compounds of the present invention may beobtained by a number of routes. For example, compounds of formula II maybe prepared according to the routes shown in Schemes 8 and 9.

Where het, n, p, Y, A, and R¹⁰ are as described supra, compounds offormula II may be prepared according to Scheme 10.

Compounds of formula XI may be converted to the corresponding acidhalide by methods well known to one skilled in the art. Compounds offormula II may be prepared by dissolving or suspending an acid halide ofa compound of formula XI in a suitable solvent and adding a compound offormula XII in a suitable solvent. Triethylamine or dimethylformamide isa convenient solvent and is typically preferred for the compound offormula XI. A 1:1 mixture of DMF and dichloromethane is a convenientsolvent and is typically preferred for the amine of formula XII. Thisamide forming reaction is also preferably run in the presence of4-dimethylaminopyridine (DMAP).

For compounds in which het is pyrazole, the addition of1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) tothe reaction is preferred. The compound of formula XI is preferably thecorresponding carboxylic acid and is employed in an equimolar amount,relative to the compound of formula XII, but a slight excess (about a0.05 to about 0.15 molar excess) is acceptable. DMAP is employed in acatalytic fashion. For example, about 5 molar percent to about 15 molarpercent, relative to the compound of formula XII, is typically employed.A 10 molar percent is usually preferred.

Compounds of formula XII where Y is —E—C(O)R³, —E—NR⁴Pg, or—E—O(CH₂)2NR⁴-Pg, which are used to prepare compounds of formula I(l),I(n), I(f), and I(h) are well known in the art and to the extent notcommercially available, are readily synthesized-by standard procedurescommonly employed in the art.

Compounds of formula XII(a) where Y is —E—NR⁴R⁵ and p, n, A, E, R⁴, andR⁵ are as described supra can be prepared as illustrated in Scheme 11from compounds of formula (i) wherein Y is —E—C(O)R³ and R³ is hydrogen.

Compounds of formula XII(a) may be prepared from compounds of formula(i) in a manner similar to that as taught in the Larock reference atpages 421-430. For an example of this transformation, see Preparation124. Compounds of formula (i) are well known in the art and to theextent not commercially available, are readily synthesized by standardprocedures commonly employed in the art.

Compounds of formula XII(c), XII(d), and XII(e) where Y is —E—S(O)qR³,and R³, p, A, and E are as described supra can be prepared asillustrated in Scheme 12.

Compounds of formula XII(c) may prepared from compounds of formula (iv)by methods well known to the skilled artisan. One manner is to combinethe compound of formula (iv) with sodium hydride in an appropriatesolvent, preferably dimethylformamide, and combining with theappropriate thiol. The compound of formula XII(c) may be furtheroxidized to form the compounds of formulas XII(d) and XII(e) in a mannersimilar to that as taught in Preparation 175 and Examples 368, and467-468. Compounds of formula (iii) can be converted to compounds offormula (iv) in a manner similar to that of Preparation 169. Compoundsof formula (iii) are well known in the art and to the extent notcommercially available, are readily synthesized by standard procedurescommonly employed in the art.

Furthermore, the transformations described in Schemes 3-8 may beperformed before the cyclization described in Scheme 1 and 2 to providethe compounds of formula XI with a fully elaborated R substituent.Additionally, the skilled artisan would appreciate that thetransformations of Schemes 11-13 may be performed after the cyclizationdescribed in Schemes 1 and 2.

Additionally, compounds of formula XII may be prepared according to thefollowing routes where, unless otherwise provided, R^(b) is thesubstituent from the carbon atom of het, R^(a) is the substituent fromthe saturated nitrogen of het, the second heteroatom is an oxygen orsulfur, and other variables are as described supra.

Compounds of formula XI(a), where het is [4,3-c]isoxazole, may beprepared in a manner similar to that described in the literature, forexample, see Chen Y P, et. al, Heterocycles, 1995, 41, 175, andChantegrel B, et. al, J. Org. Chem., 1984, 49, 4419-4424.

Compounds of formula XVI may be prepared by dissolving or suspending acompound of formula XV and a suitable base in a suitable solvent andadding a compound of formula XIV in a suitable solvent, dropwise.Toluene is a convenient solvent and is typically preferred.Triethylamine is the preferred base. The compound of formula XIV istypically and preferably employed in an equimolar amount, relative tothe compound of formula XV, but a slight excess is acceptable.

The reactants are preferably combined at about 0° C. and the resultingsolution is typically warmed to room temperature and mixed for fromabout 18 hours to about 24 hours.

The compound of formula XVI may then be converted to the compound offormula XIII by dissolving or suspending a compound of formula XVI in asuitable acidic solvent and adding hydroxylamine hydrochloride. Glacialacetic acid is a convenient acidic solvent and is typically preferred.The ester group is then hydrolyzed to the corresponding carboxylic acidof formula XI(a) through standard procedures commonly employed in theart, see for example, Larock, pgs 981-985.

The reactants are preferably combined at about room temperature thenheated to reflux for from about 30 minutes to about 60 minutes.Preferably the reaction is heated to reflux from about 40 to 45 minutes.

Compounds of formula XIV and XV are known in the art and, to the extentnot commercially available, are readily synthesized by standardprocedures commonly employed in the art.

Compounds of formula XI(b) and (c), wherein het is [4,5-c]isoxazole, maybe prepared according to route 2.

Generically, the compound of formula XVIII and hydroxylaminehydrochloride are suspended or dissolved in a suitable solvent and asuitable base is added. After the reaction is complete, the solution isacidified with a suitable acid and the resulting oxime is purified byknown methods. Typically a preferred and convenient solvent iswater/methanol. Typically a preferred and convenient base is sodiumhydroxide.

The reactants are preferably combined at about 0° C. and the resultingsolution is typically mixed for about 1 hour at about 25-30° C., untilthe reaction is complete. After the reaction is complete, the solutionis acidified with a suitable acid, preferably hydrochloric acid, and theresulting oxime is purified by known methods.

The purified oxime is dissolved or suspended in a suitable solvent,preferably DMF, and is then reacted with N-chlorosuccinimide (NCS).Preferably, NCS is added in small portions to control the expectedexotherm. The initial NCS addition results in a slight temperaturedecrease. If the reaction does not self-initiate within about 10minutes, as indicated by a slight temperature rise, hydrogen chloridemay be bubbled into the DMF solution. If the reaction does not beginwithin about 10 to 15 minutes, heating the solution to about 45-60° C.is desirable. Once the reaction begins, the temperature is preferablymaintained below about 35° C. for benzaldoximes with electron-donatingsubstituents and below about 50° C. for strong electron-withdrawingsubstituents. Completion of the reaction is indicated by cessation ofthe exotherm.

The compound of formula XIX is then converted to the compound of formulaXX by methods well known to the skilled artisan. The compound of formulaXIX and an appropriate methyl-2-butynoate are dissolved or suspended ina suitable solvent, preferably ethyl ether, and Et₃N is added. Thereactants are combined at about room temperature and mixed from about 12to 24 hours, until the reaction is complete.

The ester group of the compounds of formula XX is then hydrolyzed to thecorresponding carboxylic acid of formula XI(b) through standardprocedures commonly employed in the art, see for example, Larock, pgs981-985.

Compounds of formula XIX may be prepared in a manner similar to thatdescribed in the literature, for example, see Liu K, Shelton B R, Howe,R K, J. Org. Chem., 1980,45, 3916-3918.

Compounds of formula XXI may be prepared in a manner similar to thatdescribed in the literature, for example, see Stevens R L, Albizati K F,Tetrahedront Lett. 1984,25,4587. For an example of this transformation,see Preparation 3.

Compounds of formula XI(c) may be prepared from compounds of formula XXIin a manner similar to that described in the literature, for example,see Micetich R G, Chin C G, Can. J. Chem. 1970, 48, 1371. For an exampleof this transformation, see Preparation 4.

Compounds of formula XVIII are known in the art and, to the extent notcommercially available, are readily synthesized by standard procedurescommonly employed in the art.

The isoxazole compounds of formula XI may be converted to theisothiazole by methods well known in the art, for example see McGregor DN, Corbin U, Swigor J E, and Cheney L C, “Synthesis of isothiazoles: Thetransformation of isoxazoles into isothiazoles,” Tetrahedron, 1969, 25,389-395.

Compounds of formula XI(d) where het is pyrazolyl may be prepared asillustrated below.

Compounds of formula XXIII may be prepared by combining the compound offormula XXII with ethyl trifluoroacetyl vinyl ether in a manner similarto that described in the literature, for example, see Kamitori et al, J.Het. Chem., 1993, 30, 389. For examples of this transformation, seePreparations 7-8.

Additionally, compounds of formula XXII may be prepared from aldehydehydrazones and ethyl propiolate as is further described by Kamitori etal, Heterocycles, 1994, 38, 21.

The trifluoromethyl ketone of formula XXIII may be converted to thecorresponding carboxylic acid of formula M(d) in a manner similar tothat described in the literature, for example, see Delgado A, Clardy J,Tetrahedron Lea. 1992, 33, 2789-2790.

Compounds of formula XXII are known in the art and, to the extent notcommercially available, are readily synthesized by standard procedurescommonly employed in the art.

Compounds of the invention where het is oxazolyl or imidazolyl may beprepared as illustrated below.

Compounds of formula XI(e) may be prepared in a manner similar to thatdescribed in the literature, for example, see Nunami et al, J. Org.Chem. 1994, 59, 7635-7642.

The compound of formula XXV is converted to the compound of formulaXXVIII by methods well known to the skilled artisan. The compound offormula XXV is dissolved or suspended in a suitable solvent, preferablytetrahydrofuran, and a base is added, preferably Et₃N. The reactants arecombined at about room temperature, preferably under an inertatmosphere, and mixed from about 30 minutes to 2 hours, until thereaction is complete.

The ester group of the compounds of formula XXVIII is then hydrolyzed tothe corresponding carboxylic acid formula XI(f) through standardprocedures commonly employed in the art, see for example, Larock, pgs981-985.

Compounds of formula XIV and XXIV are known in the art and, to theextent not commercially available, are readily synthesized by standardprocedures commonly employed in the art.

Compounds of the invention where het is imidazolyl may, additionally, beprepared as illustrated below:

The compound of formula XI(e)′ may be prepared by methods well known inthe art. For specific conditions, see the preparation section(preparations 400-405).

The pharmaceutical salts of the invention are typically formed byreacting a compound of formula I with an equimolar or excess amount ofacid or base. The reactants are generally combined in a mutual solventsuch as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol,benzene, and the like for acid addition salts, or water, an alcohol or achlorinated solvent such as dichloromethane for base addition salts. Thesalts normally precipitate out of solution within about one hour toabout ten days and can be isolated by filtration or other conventionalmethods.

Acids commonly employed to form pharmaceutical acid addition salts areinorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, phosphoric acid, and the like, and organic acidssuch as p-toluenesulfonic, methanesulfonic acid, ethanesulfonic acid,oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid,citric acid, tartaric acid, benzoic acid, acetic acid, and the like.Preferred pharmaceutical acid addition salts are those formed withmineral acids such as hydrochloric acid, hydrobromic acid, and sulfuricacid, and those formed with organic acids such as maleic acid, tartaricacid, and methanesulfonic acid.

Bases commonly employed to form pharmaceutical base addition salts areinorganic bases, such as ammonium or alkali or alkaline earth metalhydroxides, carbonates, bicarbonates, and the like. Such bases useful inpreparing the salts of this invention thus include sodium hydroxide,potassium hydroxide, ammonium hydroxide, potassium carbonate, sodiumcarbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide,calcium carbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

It should be recognized that the particular counterion forming a part ofany salt of this invention is not of a critical nature, so long as thesalt as a whole is pharmacologically acceptable and as long as thecounterion does not contribute undesired qualities to the salt as awhole.

The optimal time for performing the reactions of Schemes 1-8 and Routes1-5 can be determined by monitoring the progress of the reaction viaconventional chromatographic techniques. Furthermore, it is preferred toconduct the reactions of the invention under an inert atmosphere, suchas, for example, argon, or, particularly, nitrogen. Choice of solvent isgenerally not critical so long as the solvent employed is inert to theongoing reaction and sufficiently solubilizes the reactants to effectthe desired reaction. The compounds are preferably isolated and purifiedbefore their use in subsequent reactions. Some compounds may crystallizeout of the reaction solution during their formation and then collectedby filtration, or the reaction solvent may be removed by extraction,evaporation, or decantation. The intermediates and final products offormula I may be further purified, if desired by common techniques suchas recrystallization or chromatography over solid supports such assilica gel or alumnina.

The skilled artisan will appreciate that not all substituents arecompatible with all reaction conditions. These compounds may beprotected or modified at a convenient point in the synthesis by methodswell known in the art.

PREPARATION 1 2-((1R,3R)-3-Hydroxycyclohexyl)malonic Acid Dibenzyl Ester

To a −78° C. solution of 2-(1(R)-3-oxo-cyclohexyl)malonic acid dibenzylester (see Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.;Shibasaki, M. Chem. Eur. J. 1996, 2, 1368-1372.) (3.80 g, 10.0 mmol) inTBF (50 mL) under N₂ was added L-selectride (11.0 mL at 1.0 M, 11.0mmol) dropwise and the mixture was stirred for 2 h at −78° C. EtOAc (100mL) and H₂O (100 mL) were added and the mixture was warmed to roomtemperature. Dilution with more EtOAc followed by washing with 1N NaOH,saturated NH₄Cl, brine, drying (MgSO₄), and column chromatography(silica gel, hexanes:EtOAc gradient) gave title compound (2.92 g, 76%).Mass spectrum (ES−)(m/z) 381.2 [M−1].

PREPARATION 2 (1R,3R)-(3-Hydroxycyclohexyl)acetic Acid Benzyl Ester

A solution of a compound from preparation 1 (2.30 g, 6.02 mmol), LiCl(0.511 g, 12.0 mmol), H₂O (0.217 mL, 12.0 mmol), and DMSO (20 mL) waslowered into a 165° C. oil bath for 2 h. The reaction was cooled to roomtemperature and diluted with EtOAc. Washing with H₂O and brine, drying(MgSO₄), and column chromatography (silica gel, hexanes: EtOAc gradient)gave title compound (1.12 g, 75%).

¹H NMR (CDCl₃, 400 MHz) δ 7.34−7.25 (m, 5H), 5.06 (s, 2H), 4.02 (m, 1H),2.21 (m, 2H), 1.71−1.59 (m, 4H), 1.50−1.40 (m, 41), 1.30 (m, 1H), 1.00(m, 1H) ppm.

PREPARATION 3 (1R,3S)-(3-Azidocyclohexyl)acetic Acid Benzyl Ester

To a solution of a compound from preparation 2 (1.05 g, 4.24 mmol),triphenylphosphine (1.33 g, 5.07 mmol), and hydrazoic acid (6.4 mL, at1.0 M, 6.4 mmol) in toluene (7 mL) was added DEAD (1.0 mL, 6.4 mmol)dropwise and stirred for 20 min. The mixture was diluted with EtOAc,washed with 0.1 N NaOH, H₂O and brine, dried (MgSO₄), andchromatographed (silica gel, hexanes: EtOAc gradient) to give the titlecompound (0.916 g, 80%).

PREPARATION 42-((1R,3S)-3-Azidocyclohexyl)-N-(3,4,5-trimethoxyphenyl)acetamide

A solution of a compound from preparation 3 (215 mg, 0.788 mmol) andNaOH (0.32 mL at SM, 1.6 mmol) in MeOH (5 mL) was heated at 50-55° C.for 3 h then cooled to room temperature. The reaction was diluted withH₂O and acidified with aqueous HCl to pH 2. Extraction with EtOAc andsubsequent washing (brine) and drying (Na₂SO₄) gave the crude carboxylicacid. A mixture of the crude acid, 3,4,5-trimethoxyaniline (288 mg, 1.58mmol), EDCI (262 mg, 1.58 mmol), DMAP (20 mg, 0.16 mmol) in CH₂Cl₂ (5mL) was stirred for 17 h. The mixture was diluted with CH₂Cl₂ andextracted with 1N HCl and brine then dried (MgSO₄). Columnchromatography (silica gel, hexanes: EtOAc gradient) gave the titlecompound (255 mg, 93%). Mass spectrum (ES+) (m/z) 349.2 [M+1]. MS (ES+):[M+1]349.2 m/z.

PREPARATION 52-((3S,1R)-3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)-N-3,4,5-trimethoxyphenyl)acetamide

A mixture of a compound from preparation 4 (250 mg, 0.72 mmol), 10%palladium on carbon (76 mg, 0.07 mmol), and EtOH (5 mL) was stirredunder an atmosphere of hydrogen (balloon). After 2 h the reaction wasfiltered through a pad of celite with the aid of MeOH and concentrated.Benzene was added to the resulting residue followed by concentration.The residue was dissolved in CH₂Cl₂ (5 mL) followed by addition of3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (236mg, 0.87 mmol) and DMAP (175 mg, 1.44 mmol) and stirred for 16 h. Themixture was applied to a silica gel column and elution (hexanes: EtOAcgradient) gave the title compound (256 mg, 64%). Mass spectrum (ES+)(m/z) 560.2 [M+1].

PREPARATION 6 N-(3,4,5-Trimethoxyphenyl)-2-(3-oxocyclopentyl)acetamide

To a solution of 1.0 g (7 mmol) of 3-oxocyclopentyl acetic acid indichloromethane (18 mL) and DMP (1 mL), was added 0.68 mL (7.7 mmol)oxalyl chloride. After 30 min, the solvent was removed in vacuo. Theresidue was dissolved in dichloromethane (20 mL), cooled to 0-5° C., and1.29 g of 3,4,5-trimethoxyaniline (0.63 mmol) was added followed by 0.68mL of pyridine (8.4 mmol). After 15 min, the reaction was allowed towarm to ambient temperature. After 2 h, the reaction was rinsed with 1NHCl, followed by aq. sodium bicarbonate, and water (3×). The organiclayer was dried, the solvent removed in vacuo and the residuechromatographed on a silica gel with 2% methanol in methylene chlorideto yield 0.25 g of the title compound. MS(ES+)m/z=308.

PREPARATION 7N-(3,4,5-Trimethoxyphenyl)-2-(3-hydroxycyclopentyl)acetamide

A solution of 1.07 g (3.5 mmol) of a compound from preparation 6 and0.136 g of sodium borohydride (3.5 mmol) in methanol (60 mL) was stirred12 h. The solvent was removed in vacuo, the residue dissolved in ethylacetate and rinsed with 1N HCl followed by water. The organic layer wasdried and concentrated in vacuo. The residue was chromatographed onsilica gel and eluted with 5% methanol in dichloromethane to yield 0.45g of the title compound. MS(ES+)m/z=310. Cis/trans racemic

PREPARATION 8N-(3,4,5-Trimethoxyphenyl)-2-(3-methylsulfonyloxycyclopentyl)acetamide

A solution of 0.45 g (1.46 mmol) of a compound from preparation 7 and0.135 mL (1.75 mmol) of methanesulfonyl chloride and 0.27 mL (1.9 mmol)of triethylamine in dichloromethane (15 mL) was stirred 2 h. The solventwas removed in vacuo and replaced with ethyl acetate. The organic layerwas rinsed with 1N HCl followed by aq. sodium bicarbonate, then brineand dried to yield 0.115 g of the title compound.

MS(ES+)m/z=387.9.

PREPARATION 9 N-(3,4,5-Trimethoxyphenyl)-2-(3-azidocyclopentyl)acetamide

A solution of 0.6 g (1.55 mmol) of a compound from preparation 8, and0.21 g (4.3 mmol) of lithium azide in DMF (12 mL) was stirred 12 h.Water and ice were added to the reaction, and the mixture was extractedwith ethyl acetate. The organic layer was washed 5 times with water,dried, concentrated in vacuo, and the residue was chromatographed onsilica gel and eluted with hexane/ethyl acetate 3:2 to yield 0.13 g ofcis and 0.21 g of trans of the title compound. MS(ES+) m/z=335.

PREPARATION 10cis-N-(3,4,5-Trimethoxyphenyl)-2-(3-aminocyclopentyl)acetamide

To a solution of 0.13 g (0.39 mmol) of a cis compound from preparation 9in ethyl acetate (30 mL) was added 0.026 g of 10% palladium on carbonand the mixture was hydrogenated at 50 psi over 1.5 h. The catalyst wasremoved by filtration over celite and the solvent was removed in vacuoto yield 0.128 g of the title compound. MS(ES+) m/z=309. Cis (racemic)

PREPARATION 11trans-N-(3,4,5-trimethoxyphenyl)-2-(3-aminocyclopentyl)acetamide

In the same manner as the preparation 10, 0.21 g of a tans compound frompreparation 9 was converted to 0.20 g of the title compound.MS(ES+)m/z=309. Trans (racemic)

PREPARATION 122-(3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclopentyl)-N-(3,4,5-trimethoxyphenyl)acetamide

A solution of 0.123 g (0.42 mmol)of a compound from preparation 10, 0.03g (0.46 mmol) of3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride, and0.07 mL (0.5 mmol) of triethylamine in dichloromethane (10 mL) wasstirred for 12 h. The solvent was removed in vacuo and replaced withethyl acetate. The organic layer was washed with 1N HCl, then aq.NaHCO₃, followed by brine and dried. The solvent was removed in vacuo toyield 0.255 g of the title compound. MS(ES+) m/z=545.8. cis (racemic)

PREPARATION 132-(3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclopentyl)-N-(3,4,5-trimethoxyphenyl)acetarmide

In the same manner as preparation 12, 0.2 g (0.65 mmol) of a compoundfrom preparation 11 was converted to 0.324 g of the title compound.MS(ES+)m/z=545.8. Racemic

PREPARATION 14 N-((1S,3R)-3-Cyanomethylcyclopentyl)(t-butoxy)carboxamide

To a solution of 8.2 g (0.0222 mol) ofN-[t-butoxycarbonyl]-2-(p-toluenesulfonyloxymethyl)cyclopentylamine inDMF (250 mL) was added 3.3 g (0.067 mmol) of NaCN and the suspension washeated at 80° C. for 4 h. The solvent was removed in vacuo at 40° C. andthe residue was slurried in brine. The aqueous layer was extracted withethyl acetate, dried and the solvent was removed in vacuo to yield 5.7 gof the title compound. MS(ES+)m/z=225. (one enantiomer)

PREPARATION 15 2-{(3S,1R)-3-[(t-Butoxy)carbonylamino]cyclopentyl}aceticAcid

A suspension of 2.0 g (8.9 mmol) of a compound from preparation 14 in 3NKOH (32 mL) and EtOH (12 mL) was heated at reflux for 6 h (solution).The alcohol was removed in vacuo and the reaction was cooled andneutralized with 3N HCl. The product was separated by filtration, rinsedwith water and dried in vacuo at 40° C. to yield 1.33 g of the titlecompound.

MS(ES+)m/z=244.

PREPARATION 162-{(3S,1R)-3-[(t-Butoxy)carbonylamino]cyclopentyl-N-(3,4,5-trimethoxyphenyl)acetamide

To a solution of 0.1 g (0.4 mmol) of a compound from preparation 15 inTBF/DMF 1:1 (5 mL) was added 0.061 g (0.44 mmol) of1-hydroxy-7-azabenzotriazole and 0.086 g (0.44 mmol) of EDCI. After 40min, 0.083 g (0.44 mmol) of 3,4,5-trimethoxyaniline was added. After3.25 h, the solvent was removed in vacuo and replaced with ethylacetate. The organic layer was rinsed with 1N HCl, aq. NaHCO₃, then 3×with water. The organic layer was dried and the solvent was removed invacuo to yield 0.144 g of the title compound. MS(ES+)m/z=409.

PREPARATION 172-((3S,1R)-3-Aminocyclopentyl)-N-(3,4,5-trimethoxyphenyl)acetamide

A solution of 0.48 g (0.362 mmol) of a compound from preparation 16 inTFA (10 mL) was stirred for 1 h, after which the TFA was removed invacuo and replaced with ethyl acetate. The organic layer was rinsed with1N NaOH followed by brine and dried. The organic layer was removed invacuo to yield 0.3 g of the title compound.

MS(ES+)m/z=309.

PREPARATION 182-((3S,1R)-3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclopentyl)-N-(3,4,5-trimethoxyphenyl)acetamide

In the same manner as preparation 12, 0.32 g (1.04 mmol) of a compoundfrom preparation 17 yielded 0.52 g of the title compound.MS(ES+)m/z=546.

PREPARATION 19 N-(t-Butoxycarbonyl)-3-aza-2-oxabicyclo[3.2.1]nonane

A solution of 0.59 g (4.8 mmols) of 2-oxo-3-azabicyclo-[3.2.1]nonane,2.07 g (9.6 mmol) of (BOC)₂O and 1.173 g (9.6 mmol) of DMAP in CH₂Cl₂(15 mL) was stirred 12 h. The solvent was removed in vacuo and replacedwith ethyl acetate. The organic layer was rinsed with 1N HCl followed bybrine, dried and the solvent removed in vacuo to yield 0.495 g of thetitle compound. MS(ES+)m/z=225.9

PREPARATION 20cis-3-{[(t-Butoxy)carbonylamino]methyl}cyclopentanecarboxylic Acid

To a solution of 2.22 g (0.98 mmol) of a compound from preparation 19 inTBF (113 mL) was added H₂O (32 mL) and the solution cooled to 5° C.Water (30%, 11.95 mL, 9.8 mmol) was added followed by 2.08 g (4.9 mmol)of LiOH and the reaction was allowed to warm to ambient temperature.After 2 h, the reaction was quenched with sodium sulfite solution (10%)and the THF was removed in vacuo. With cooling, the reaction wasacidified with 6N HCl and extracted with ethyl acetate, dried and thesolvent removed in vacuo to yield 1.583 g of the title compound.MSES+)m/z=243.9.

PREPARATION 21cis-N-(3-{[(t-Butoxy)carbonylamino]methyl}cyclopentyl)(phenylmethoxy)carboxamide

To warm solution of 0.244 g (1.0 mmol) of a compound from preparation 20in toluene (8 mL) was added 0.2 mL (1.4 mmol) of Et₃N followed by 0.3 mL(1.4 mmol) of diphenylphosphoryl azide. The reaction was stirred atambient temperature for 2.5 h and refluxed for 1.5 h. The solvent wasremoved in vacuo and replaced with ethyl acetate which was rinsed withaq. NaHCO₃, aq. KHSO₄ and brine. The solvent was removed in vacuo andthe residue was chromatographed on silica gel with 0.5-1% MeOH/CH₂Cl₂ toyield 0.264 g of the title compound. MS(ES+)m/z=349.

PREPARATION 22

cis-N-[(3-Aminocyclopentyl)methyl](t-butoxy)carboxamide

A suspension of 0.264 g (0.76 mmol) of a compound from preparation 21and 0.034 g of Pd/C 10% in MeOH (40 mL) was reduced at 1.0 atm. of H₂over 2.5 h. The catalyst was removed by filtration and the solvent wasremoved in vacuo to yield 0.187 g of the title compound. MS(ES+)m/z=215.

Preparation 23cis-N-[(3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclopentyl)methyl](t-butoxy)carboxamide

To a suspension of 0.187 g (0.873 mmol) of a compound from preparation22 in dichloromethane (10 mL) was added 0.263 g (0.96 mmol) of3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloridefollowed by 0.2 mL (1.4 mmol) of Et₃N. After 70 min, the solvent wasremoved in vacuo and replaced with ethyl acetate. The organic layer wasrinsed with 1N HCl followed by aq. NaHCO₃, dried and the solvent wasremoved in vacuo to give a residue which was chromatographed on silicagel with hexane/ethyl acetate 3-1 to yield 0.156 g of the titlecompound. MS(ES+)m/z=452.

Preparation 24cis-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclopentyllmethyl}(t-butoxy)carboxamide

To a solution of 0.136 g (0.3 mmol) of a compound from preparation 23 inDMF (7.0 mL) at 0-5° C. was added 0.6 mL (0.3 mmol) of KHMDS (0.5N inTHF). After 2 min, cooling was removed. After 3 additional min, 1N HClwas added and the mixture was extracted with ethyl acetate. The organiclayer was rinsed with water, dried and concentrated to a foam in vacuowhich was chromatographed on silica gel with hexane/ethyl acetate 3:1 toyield 0.057 g of the title compound. MS(ES+)m/z=432.

PREPARATION 25 2-(3-Aminocyclopentyl)ethanenitrile

In the same manner as preparation 17, 0.3 g (4.5 mmol) of a compoundfrom preparation 14 was deprotected with TFA to yield 0.087 g of thetitle compound.

MS(ES+)m/z=125.

PREPARATION 26N-[(1R,3S)-3-(cyanomethyl)cyclopentyl][3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

In the same manner as preparation 18, 0.08 g (0.65 mmol) of a compoundfrom preparation 26 was acylated with3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride toyield a residue which after chromatography on silica gel withhexane/ethyl acetate 1:1 yielded 0.177 g of the title compound.MS(ES+)m/z=362.

PREPARATION 272-[(3S,1R)-3-(9-chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclopentyl]ethanenitrile

In the same manner as preparation 24, 0.166 g (0.46 mmol) of a compoundfrom preparation 27 was cyclized to a residue which upon chromatographyon silica gel with hexane/ethyl acetate 2:1 yielded 0.099 g of the titlecompound. MS(ES+)m/z=342.

PREPARATION 282-[(3S,1R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclopentyl]aceticAcid

A suspension of 0.086 g (0.25 mmol) of a compound from preparation 27 inHCl conc. (40 mL) was refluxed for 6 h, after which the reaction wasconcentrated to a residue in vacuo at 40° C. The residue was taken intodiethyl ether, the insolubles filtered and discarded, and the filtratewas extracted with 1N NaOH. The basic layer was acidified with 1N HCl,extracted with ethyl acetate, dried and concentrated in vacuo to yield0.059 g of the title compound. MS(ES+)n/z=361.

PREPARATION 29N-[3(1S,3S)-3-(2-aminoethyl)cyclopentyl](t-butoxy)carboxamide

0.5 g (2.2 mmols) of a compound from preparation 14 was reduced with0.065 g of PtO₂ in EtOH (50 mL) at 60 psi of H₂ at 40° C. over 12 h. Thecatalyst was removed by vacuum filtration, and the solvent was removedin vacuo to yield 0.421 g of the title compound. MS(ES+)m/z=229.

PREPARATION 30N-{(1S,3S)-3-[2-(Phenylcarbonylaniino)ethyl]cyclopentyl}(t-butoxy)carboxamide

In a manner similar to the acylation of a compound from preparation 24,0.172 g (0.75 mmol) of a compound from preparation 29 was acylated withbenzoyl chloride and the residue formed was chromatographed on silicagel with hexane/ethyl acetate 2:1 to yield 0.127 g of the titlecompound. MS(ES+)m/z=333.

PREPARATION 31 N-{(1S,3S)-3-[2-(Phenylcarbonylamino)ethyl]cyclopentyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

In a manner similar to preparation 17, 0.127 g (0.36 mmol) of a compoundfrom preparation 30 was deprotected, followed by acylation with3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride in thesame manner as the preparation of a compound from preparation 12 toyield 0.15 g of the title compound. MS(ES+)m/z=470.

PREPARATION 32N-((1S,3S)-3-{2-[(3,4,5-Trimethoxyphenyl)carbonylamino]ethyl}cyclopentyl)(t-butoxy)carboxamide

In the same manner as preparation 30, 0.1 g (0.44 mmol) of a compoundfrom preparation 29 was acylated with 3,4,5-trimethoxybenzoyl chlorideto yield 0.16 g of the title compound. MS(ES+)m/z=423.

PREPARATION 33N-{(1S,3S)-3-[2-((3,4,5-Trimethoxyphenyl)carbonylamino)ethyl]cyclopentyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

In a manner similar to preparation 31, 0.16 g (0.38 mmol) of a compoundfrom preparation 32 yielded 0.174 g of the title compound.MS(ES+)m/z=560.

PREPARATION 34 ((3S,1R)-3-{[(t-Butoxy)carbonylamino]methyl)cyclopentyl)-N-(3,4,5-trimethoxyphenyl)carboxamide

In a manner similar to the preparation of a compound from preparation16, 0.224 g (0.92 mmols) of a compound from preparation 20 was convertedto 0.34 g of the title compound. MS(ES+)m/z=409.

PREPARATION 35 [(3S,1R)-3-(aminomethyl)cyclopentyl]-N-(3,4,5-trimethoxyphenyl)carboxamide

In a manner similar to preparation 17, 0.049 g (0.12 mmol) of a compoundfrom preparation 34 was deprotected with TFA to yield 0.013 g of thetitle compound. MS(ES+)m/z=308.

PREPARATION 36[(3S,1R)-3-({[3-2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}methyl)cyclopentyl]-N-(3,4,5-trimethoxyphenyl)carboxamide

In a manner similar to preparation 18, 0.013 g (0.042 mmol) of acompound from preparation 35 was converted to a residue which waschromatographed on silica gel with dichloromethane 100% todichloromethane/MeOH 2% to yield 0.018 g of the title compound.MS(ES+)m/z=545.8.

PREPARATION 37 Ethyl2-(3-{[4-(2-chloro-6-fluorophenyl)-2-methyl-3-furyl]carbonylamino}cyclohexyl)acetate

To a solution of 3-nitrophenylacetic acid, 1.0 g (5.5 mmol) in 90 mL ofethanol was added 1.0 g of PtO₂ and 2 mL of 5N HCl. The mixture washydrogenated overnight at 60° C. and 60 psi, filtered through celite andconcentrated to dryness. To a solution of the residue in 15 mL ofdichloromethane was added 3.0 mL (21.6 mmol) of triethylamine and 2.0 g(7.2 mmol) of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonylchloride. The solution was stirred overnight at ambient temperature.Chloroform was added and the solution was washed with 0.5N HCl,saturated sodium bicarbonate, brine, dried over sodium sulfate, filteredand concentrated to dryness. The residue was chromatographed on silicagel using 5% acetone/dichloromethane as eluent to yield 2.0 g (66%) ofthe desired mixture of isomers as a white solid. ¹H—NMR is consistentwith structure. MS (ion spray) 423.2 (M+1).

PREPARATION 38 Ethyl2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]acetate

To a solution of a compound from preparation 37, 1.0 g (2.4 mmol) in 20mL of N,N-dimethylformamide was added 0.35 g (3.1 mmol) of potassiumt-butoxide. After 75 min, the mixture was poured into 1N HCl/ice andextracted with ethyl acetate. The combined organics were washed withbrine, dried over sodium sulfate, filtered and concentrated to dryness.The residue was chromatographed on silica gel using 5%acetone/dichloromethane as eluent to yield 0.65 g (67%) of the desiredmixture of isomers as a viscous yellow oil. ¹H—NMR is consistent withstructure. MS (ion spray) 403.3 (M+1).

PREPARATION 392-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]aceticAcid

To a solution of a compound from preparation 38, 0.65 g (1.5 mmol) in 10mL of tetrahydrofuran and 10 mL of ethanol was added 3.0 mL (15.0 mmol)of 5N sodium hydroxide. After 40 min at ambient temperature, thereaction was concentrated to dryness. The residue was partitionedbetween ethyl acetate and water, was acidified to pH 3.0 with 1N HCl,and was extracted with ethyl acetate. The combined organics were washedwith brine, dried over sodium sulfate, filtered and concentrated todryness to yield 0.53 g (93%) of the desired mixture of isomers as awhite foam. ¹H−NMR is consistent with structure. MS (ion spray) 375.2(M+1).

PREPARATION 40 Methyl 2-(3-nitrocyclohexyl)acetate

To a solution of m-nitrophenylacetic acid, 14.2 g (78.0 mmol) in 200 mLof methanol at 0° C. was added 20 mL of acetyl chloride dropwise. Thereaction mixture was stirred overnight at ambient temperature andconcentrated to dryness. The residue was chromatographed on silica gelusing 50% ethyl acetate/hexanes as eluent to yield 14.7 g (97%) of thedesired mixture of isomers as a yellow oil. ¹H—NMR is consistent withstructure. MS (FD) 194.8 (M−1).

PREPARATION 41 Methyl2-(3-{[4-(2-chloro-6-fluorophenyl)-2-methyl-3-furyl]carbonylamino}cyclohexyl)acetate

To a solution of methyl 2-(3-nitrocyclohexyl)acetate (13.8 g, 71.0 mmol)in 200 mL of acetic acid was added 6.9 g of PtO₂. The mixture washydrogenated overnight at ambient temperature and 60 psi, then wasfiltered through celite and concentrated to dryness. To a solution ofthe residue, 8.8 g (38.0 mmol) in 200 mL of dichloromethane was added 27mL (190 mmol) of triethylamine and 10.4 g (38.0 mmol) of3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride. Themixture was stirred overnight at ambient temperature then chloroform wasadded. The organics were washed with 0.5N HCl, saturated sodiumbicarbonate, brine, dried over sodium sulfate, filtered and concentratedto dryness. The resulting residue was chromatographed on silica gelusing 5% acetone/dichloromethane to yield 4.43 g (29%) of the desiredmixture of isomers as a colorless, viscous oil. ¹H—NMR is consistentwith structure. MS (ion spray) 409.2 (M+1).

PREPARATION 422-(3-{[4-(2-Chloro-6-fluorophenyl)-2-methyl-3-furyl]carbonylamino}cyclohexyl)aceticAcid

To a solution of a compound from preparation 41, 1.2 g (3.0 mmol) in 20mL of absolute ethanol and 20 mL of tetrahydrofuran was added 6.0 mL(30.0 mmol) of 5N sodium hydroxide. The mixture was stirred 4 h, thenthe organics were concentrated off. The remaining aqueous phase wasacidified to pH 3.0 with 1N HCl, then extracted with ethyl acetate. Thecombined organics were washed with brine, dried over sodium sulfate,filtered and concentrated to dryness. The residue was dissolved inchloroform and concentrated to dryness to yield 1.0 g (84%) of thedesired mixture of isomers as a white foam. ¹H—NMR is consistent withstructure. MS (ion spray) 393.2 (M−1).

PREPARATION 43[4-(2-Chloro-6-fluorophenyl)-2-methyl(3-furyl)]-N-{3-[2-(4-methylpiperidyl)-2-oxoethyl]cyclohexyl}carboxamide

To a solution of a compound from preparation 42, 1.0 g (2.6 mmol) in 10mL of N,N-dimethylformamide was added 0.34 mL (2.9 mmol) of4-methylpiperidine, 0.43 g (3.1 mmol) of 1-hydroxy-7-azabenzotriazoleand 0.6 g (3.1 mmol) of1-(3-(dimethyl-amino)propyl)-3-ethylcarbodiimide. The mixture wasstirred overnight at ambient temperature and concentrated to dryness.The resulting residue was partitioned between ethyl acetate and waterand was extracted with ethyl acetate. The combined organics were washedwith brine, dried over sodium sulfate, filtered and concentrated todryness. The residue was chromatographed on silica gel using a gradientof 30% ethyl acetate/hexanes to 5% methanol/chloroform as eluent toyield 0.9 g (70%) of the desired mixture of isomers as a white foam.1H—NMR is consistent with structure. MS (ion spray) 476.2 (M+1).

PREPARATION 445-[(3S,1R)-3-(Aminomethyl)cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

A solution of a compound from preparation 54 (enantiomer 2) (6.6 g (14.8mmol) in 230 mL of acetic acid saturated with hydrochloric acid wasstirred for 2 h at ambient temperature, then was concentrated todryness. The resulting residue was partitioned between 20%isopropanol/chloroform and saturated sodium bicarbonate and wasextracted with 20% isopropanol/chloroform. The combined organics werewashed with brine, dried over sodium sulfate, filtered and concentratedto dryness to yield 4.68 g (92%) of the desired product as a yellowsolid. ¹H—NMR is consistent with structure.

MS (ion spray) 346.1 (M+1).

PREPARATION 45Phenylmethyl-2-{(3S,1R)-3-[(t-butoxy)carbonylamino]cyclohexyl}acetate

To a solution of phenylmethyl 2-((3S,1R)-3-azidocyclohexyl)acetate, 5.0g (18.3 mmol) in 350 mL of ethyl acetate under a nitrogen atmosphere wasadded 8.0 g (36.6 mmol) of BOC-anhydride and 2.0 g of Lindlar'scatalyst. The nitrogen was purged with hydrogen and the reaction mixturewas stirred overnight under a hydrogen balloon, then concentrated todryness. The resulting residue was filtered through celite andchromatographed on silica gel using ethyl acetate/hexanes as eluent toyield 6.25 g (98%) of the desired product as a clear oil whichsolidifies upon standing. ¹H—NMR is consistent with structure. MS (ionspray) 347 (M⁺).

PREPARATION 46 Phenylmethyl2-((3S,1R)-3-{[4-(2-chloro-6-fluorophenyl)-2-methyl(3-furyl)]carbonylamino}cyclohexyl)acetate

To a solution of a compound from preparation 45, 5.05 g (20.4 mmol) in80 mL of dichloromethane at 0° C. was added 3.7 mL (24.5 mmol) oftriethylamine and 10 mg of 4-dimethylaminopyridine, followed by 6.15 g(22.4 mmol) of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonylchloride. The reaction mixture was stirred overnight while warming toambient temperature, and was then washed with 0.1N hydrochloric acid,washed with brine, dried over sodium sulfate, filtered and concentratedto dryness. The residue was chromatographed on silica gel using ethylacetate/hexanes as eluent, concentrated to dryness, dissolved inchloroform and concentrated to dryness to yield 5.74 g (58%) of thedesired compound as a white solid. ¹H—NMR is consistent with structure.MS (ion spray) 485.5 (M+1).

PREPARATION 472-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]aceticAcid

To a solution of a compound from Example 491 (3.91 g, 8.4 mmol) in 70 mLof dioxane was added 70 mL (350 mmol) of 5N sodium hydroxide. Themixture was refluxed for 4 h and was cooled to ambient temperature andacidified to pH 1 with 5N hydrochloric acid. The resulting mixture wasextracted with 20% isopropanol/chloroform. The combined organics werewashed with brine, dried over sodium sulfate, filtered and concentratedto dryness. The residue was triturated in ether, filtered and driedunder vacuum to yield 1.8 g (57%) of the desired product as a tan solid.¹H—NMR is consistent with structure. MS (ion spray) 374.8 (M+).

PREPARATION 48cis-N-[3-Aminomethylcyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

A slurry of a compound from preparation 52, 1.2 g (2.7 mmol) in 20 mL ofacetic acid saturated with hydrochloric acid was stirred for 4 h atambient temperature, then concentrated to dryness. The residue wasdissolved in toluene and concentrated to dryness. The residue wasslurried in ether/hexanes, concentrated to dryness, and dried undervacuum to yield 750 mg (80%) of the title compound as a tan solid.¹H—NMR is consistent with structure. MS (ion spray) 346.2 (M+1).

PREPARATION 49 (t-Butoxy)-N-[(3-nitrophenyl)methyl]carboxamide

To a suspension of 5.00 g (26.5 mmol) of 3-nitrobenzylaminehydrochloride in 100 mL CH₂Cl₂ at room temperature was added 5.79 g(26.5 mmol) of di-t-butyl dicarbonate. To this was added 8.13 mL (58.3mmol) of triethylamine, dropwise over 15 min. The reaction was stirredfor 3 h at room temperature, after which it was diluted with 300 mL ofethyl acetate. The resulting organic solution was washed three timeswith 1N HCl solution, dried over sodium sulfate and concentrated invacuo to give 6.2 g (93%) of a white solid, which was characterized asthe-title compound. MS (FIA) m/z=253.

PREPARATION 50 (t-Butoxy)-N-[(3-aminocyclohexyl)methyl]carboxamide

To a solution containing 12.0 g (47.7 mmol) of a compound frompreparation 49 in 300 mL ethanol was added 6.0 g of rhodium on carbon.The reaction was subjected to hydrogenation (60 psi) at 60° C. for 18 h,after with the catalyst was removed by vacuum filtration and the solventremoved in vacuo, giving 9.5 g (87%) of a clear oil. This material wascharacterized as the title compound and used without furtherpurification.

PREPARATION 51N-(3{[t-Butoxy)carbonylamino]methyl}cyclohexyl)[4-(2-chloro-6-fluorophenyl)-2-methyl(3-furyl)]carboxamide

To a solution of 9.5 g (41.6 mmol) of a compound from preparation 50 in200 mL of CH₂Cl₂ was added 11.4 g (41.6 mmol) of3-(2-chloro-6-fluorophenyl)-5-methyl-isoxazole-4-carbonyl chloride,followed by 11.6 mL (83.2 mmol) of triethylamine at room temperature.The reaction was stirred at room temperature for 15 h, and concentratedin vacuo. The crude solid was dissolved in 200 mL of ethyl acetate andthe organic solution was washed twice with 1N HCl solution, dried oversodium sulfate and concentrated in vacuo to give a yellow solid. Thismaterial was recrystallized from methanol to give 12.5 g (64%) of awhite crystalline solid, which was characterized as the title compound,as an inseparable mixture of cis and trails isomers. MS(FIA) m/z =466.2.

PREPARATION 52 AND 53(t-Butoxy)-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}carboxamide

To a stirred solution of 7.00 g (15.0 mmol) of a compound frompreparation 51 in 200 mL of DMF at room temperature was added 30.0 mL(15 mmol) of a 0.5 M toluene solution of potassium bis(trimethylsilyl)amide over 10 min. The resulting dark red reaction was stirred anadditional 5 min at room temperature and added to 200 mL of 1N HCl. Thetwo phase solution was diluted with 400 mL of ethyl acetate and theorganic layer was separated. The organic solution was washed four timeswith brine, dried over sodium sulfate and concentrated in vacuo to givean orange solid. This material was recrystallized from toluene to give3.4 g of a light yellow solid, which was characterized as pure racemiccis material, 52: MS(FIA) m/z=446.1. Purification of the racemic transmaterial (53) was accomplished by concentrating the mother liquor andsubjecting this material to flash chromatography on silica gel, using50% hexane-ethyl acetate as the eluant. The major fractions werecombined to give a light yellow solid, which was characterized as pureracemic trans material: MS(FIA) m/z=446.1.

PREPARATION 54N-{3-(9-chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl-]methyl}(t-butoxy)carboxamide

The racemic cis material from a compound from preparation 52 wasseparated into its enantiomers by chiral HPLC chromatography using aChiralpak AD column and 10% ethyl alcohol-heptane as the eluant at aflow of 1.0 mL/min.

Retention Time (Enantiomer 1)=10.501 min.

Retention Time (Enantiomer 2)=12.576 min.

PREPARATION 55 Methyl 3-[4-methoxyphenyl)methoxy]benzoate

To a solution containing 5.00 g (32.9 mmol) of methyl 3-hydroxybenzoatein 100 mL of DMF was added 4.77 mL (32.9 mmol) of p-methoxybenzylchloride and 4.54 g (32.9 mmol) of anhydrous potassium carbonate. Thereaction was stirred at room temperature for 16 h, followed by 1 h at100° C. The solution was diluted with 200 mL of ethyl acetate and 200 mLof 1N HCl. The organic phase was separated and washed five times withbrine, dried over sodium sulfate and concentrated in vacuo to give 8.99g of a white amorphous solid, which was characterized as the titlecompound. This material was used without further purification.

PREPARATION 56 3-[(4-Methoxyphenyl)methoxy]benzoic Acid

To a solution containing 2.75 g (10.0 mmol) of a compound frompreparation 55 in 50 mL of MeOH was added 10 mL of 1N NaOH solution. Toaid solubility, 20 mL of THF was added and the reaction was heated atreflux for 3 h. The reaction was cooled to room temperature and dilutedwith 100 mL of ethyl acetate and 100 mL of 1N HCl solution. The organiclayer was separated, dried over sodium sulfate and concentrated in vacuoto give 2.45 g of a white amorphous solid, which was characterized asthe title compound. This material was used without further purification.

PREPARATION 57 (-)-(1R,cis)-Pinonic Acid

A solution of 1S-(-)-pinene (11.95 mL, 75 mmol) in methanol (50 mL) andchloroform (50 mL) at −78° C. was treated with ozone for 2 h via a gasdispersion tube. After purging with nitrogen for 1 h, methyl sulfide(16.5 mL, 225 mmol) was added, and the reaction was allowed to warm toroom temperature overnight. The solvent was removed in vacuo and theresidue dissolved in diethyl ether, washed with water, saturated aqueousbrine solution, dried over magnesium sulfate and concentrated toapproximately 11 g of yellow liquid. The liquid was dissolved in ethylether and treated with oxygen for 2 h, followed by stirring under an O₂balloon overnight. The reaction was concentrated to give 12.42 g as aslightly yellow liquid, 90% yield. 1H NMR: consistent with structure.

MS (ion spray) 183 (M⁻−1).

PREPARATION 58 (3-Acetylamino-2,2-dimethylcyclobutyl)acetic Acid

To a solution of a compound from preparation 57 (12.37 g, 67.1 mmol) inacetic acid (270 mL) was added hydroxylamine-O-sulfonic acid (11.74 g,100.7 mmol), and the reaction was heated to reflux under nitrogen for 20h. The reaction was concentrated and the residue dissolved in 2N HCl,followed by extraction with ethyl acetate (×4). The combined organicswere washed with brine, dried over magnesium sulfate, and concentrated.The brown solution was treated with decolorizing charcoal, filteredthrough celite, and concentrated to 5.85 g as a light yellow oil, 44%yield. ¹H NMR: consistent with structure. MS (ion spray) 200 (M⁺+1), 198(M⁺−1).

PREPARATION 59 (3-Acetylamino-2,2-dimethylcyclobutyl)acetic Acid MethylEster

To a 0° C. flask of methanol (150 mL) was added thionyl chloride (10.7mL, 146.8 mmol) dropwise via an addition funnel. To this solution wasadded a compound from preparation 58 (5.85 g, 29.4 mmol) dropwise as asolution in methanol (100 mL). The cooling bath was removed and thereaction allowed to stir at room temperature for 2 h. The reaction wasconcentrated to a brown oil, dissolved in ethyl acetate, washed withsaturated aqueous sodium bicarbonate solution, brine, dried overmagnesium sulfate and concentrated to a 5.5 g of a brown oil.Purification by column chromatography on silica gel (eluting with50-100% ethyl acetate/hexane) gave 3.1 g as a brown oil, 50% yield.

1H NMR: consistent with structure. MS (ion spray) 213 (M⁺).

PREPARATION 60 (3-Amino-2,2-dimethylcyclobutyl)acetic Acid Methyl Ester

A compound from preparation 59 (3.09 g, 14.5 mmol) was dissolved in 2NHCl (100 mL) and heated to reflux for 18 h, then concentrated. To a 0°C. flask of methanol (100 mL) was added thionyl chloride (5.3 mL, 72.4mmol) dropwise via an addition funnel. To this solution was added thecrude material dropwise as a solution in methanol (15 mL). The clearsolution was allowed to warm to room temperature overnight. The solutionwas concentrated, and purification by SCX column (eluting withtetrahydrofuran/water then ammonia/methanol) gave 2.52 g as a brownsolid, 100% yield.

¹H NMR: consistent with structure. MS (ion spray) 172 (M⁺+1).

PREPARATION 61(3-{[3-(2-Chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl]amino}-2,2-dimethyl-cyclobutyl)aceticAcid Methyl Ester

To a solution of a compound from preparation 60 (566 mg, 3.31 mmol) indichloromethane (20 mL) was added3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (1.09g, 3.97 mmol), 4-dimethylaminopyridine (40 mg, 0.33 mmol), andtriethylamine (1.4 mL, 9.92 mmol) dropwise via syringe. The solution wasstirred under nitrogen at room temperature overnight. The solution waswashed with 1.0N HCl (×3), saturated aqueous sodium bicarbonatesolution, brine, dried over magnesium sulfate and concentrated.Purification by flash chromatography on silica gel (eluting with 20-40%ethyl acetate/hexane) gave 1.28 g as a yellowish oil, 95% yield. ¹H NMR:consistent with structure. MS (ion spray) 409 (M⁺).

PREPARATION 62[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-2,2-dimethyl-cyclobutyl]-aceticAcid Methyl Ester

To a 0° C. solution of a compound from preparation 61 (2.44 g, 5.97mmol) in dimethylformamide (100 mL) was added potassium t-butoxide (0.80g, 7.16 mmol). After 15 min, the reaction was quenched with 1.0N HCl andextracted with 20% isopropanol/chloroform. The organic layer was thenwashed with 1.0N HCl (×2), saturated aqueous sodium bicarbonatesolution, brine, dried over magnesium sulfate and concentrated.Purification by flash chromatography on silica gel (eluting with 15-20%ethyl acetate/hexane) gave 739 mg (32% yield) as a white solid. ¹H NMR:consistent with structure. MS (ion spray) 389 (M⁺).

PREPARATION 63[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-2,2-dimethyl-cyclobutyl]aceticAcid

A solution of a compound from preparation 62 (737 mg, 1.89 mmol) in 5NNaOH (25 mL) was heated to reflux for 1 h. The solution wasconcentrated, dissolved in 20% isopropanol/chloroform, acidified to pH 2with 5N HCl, washed with 1.0N HCl (×2), dried over magnesium sulfate andconcentrated to give 519 mg as a light orange foam, 73% yield. ¹H NMR:consistent with structure.

PREPARATION 64[3-(9-Chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-2,2-dimethyl-cyclobutylmethyl]carbamicAcid 2-trimethylsilanylethyl Ester

To a mixture of a compound from preparation 63 (318.7 mg, 0.85 mmol) intoluene (15 mL) was added triethylamine (130 μL, 0.94 mmol),diphenylphosphorylazide (202 μL, 0.94 mmol), and the mixture heated toreflux for 3 h. To the reaction was added 2-(trimethylsilyl)-ethanol(183 μL, 1.28 mmol), and the mixture heated at reflux overnight. Thesolution was concentrated and dissolved in dichloromethane, washed with1.0N HCl, brine, dried over magnesium sulfate and concentrated.Purification by flash chromatography on silica gel (eluting with 0-30%ethyl acetate/hexane) gave 144 mg as a white foam, 35% yield. ¹H NMR:consistent with structure. MS (ion spray) 490 (M⁺).

PREPARATION 65N-3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)(t-butoxy)carboxamide

To a 0° C. solution of 1,3-diaminocyclohexane (50.56 g, 442.8 mmol) inchloroform (850 mL) was added a solution of di-t-butyl-dicarbonate (20.3mL, 88.6 mmol) in chloroform (250 mL) dropwise via an addition funnelover 25 minutes. The mixture was stirred under nitrogen at roomtemperature overnight. The reaction was washed with saturated aqueoussodium bicarbonate solution (3×), brine, dried over magnesium sulfate,and concentrated to give 17.58 g of a white oil. To a solution of thecrude material (17.58 g, 82.0 mmol) in dichloromethane (500 mL) wasadded 37(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride(23.65 g, 86.1 mmol), dimethylaminopyridine (1.00 g, 8.2 mmol), andtriethylamine (34.3 mL, 246.1 mmol) dropwise via syringe. The solutionwas stirred under nitrogen at room temperature overnight. The solutionwas washed with 0.1N HCl (2×), saturated aqueous sodium bicarbonatesolution (2×), brine, dried over magnesium sulfate and concentrated. Theorange solids were treated with ethyl ether, sonicated for 15 minutes,and filtered. The resulting white solids were crushed, treated withethyl ether, sonicated for 15 minutes, filtered out, and dried on avacuum overnight to give 16.20 g of the title racemic cis compound as awhite solid, 87% yield based on a 1:1 mixture of cis:trans. Thismaterial was then separated by chiral LC on a Chiralcel OD column toyield 9 g of isomer 1: (3S,1R) and 7 g of isomer 2: (1S,3R). ¹H NMR:consistent with structure. MS (ion spray) 352 (M⁺−BOC+1).

PREPARATION 66N-(1S,3R)-3-(9-Chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl,(t-butoxy)carboxamide

To a solution of a compound from preparation 65 (isomer 1) (500 mg, 1.11mmol) in dimethylformamide (20 mL) was added KHMDS (3.3 mL, 1.66 mmol,0.5M in toluene) rapidly via syringe. After 15 minutes, ethyl acetate(50 mL) was added to the reaction, and the solution added to aseparatory funnel containing water (50 mL) and brine (30 mL). The layerswere separated, and the aqueous layer was extracted with ethyl acetate(×2). The combined organics were washed with brine, dried over magnesiumsulfate, and concentrated to give 709 mg red solid. Purification usingflash chromatography on silica gel (eluting with 20-30% ethylacetate/hexane) gave 205 mg of the title compound as a yellow solid, 43%yield. ¹H NMR: consistent with structure. MS (ion spray) 332 (M⁺−BOC).

PREPARATION 67N-(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl(t-butoxy)carboxamide

To a solution of a compound from preparation 65 (isomer 2) (500 mg, 1.11mmol) in dimethylformamide (20 mL) was added KHMDS (3.3 mL, 1.66 mmol,0.5M in toluene) rapidly via syringe. After 4 minutes, ethyl acetate (50mL) was added to the reaction, and the solution added to a separatoryfunnel containing water (50 mL) and brine (30 mL). The layers wereseparated, and the aqueous layer was extracted with ethyl acetate (2×).The combined organics were washed with brine, dried over magnesiumsulfate, and concentrated to give 700 mg red solid. Purification usingflash chromatography on silica gel (eluting with 0-0.5%methanol/chloroform) gave 372 mg of the title compound as a yellowsolid, 78% yield. ¹H NMR: consistent with structure. MS (ion spray) 332(M⁺−BOC).

PREPARATION 685-((3S,1R)-3-Aminocyclohexyl)-9-chloro-3-methyl-H-isoxazolo[4,3-c]quinolin-4-oneHydrochloride

To a compound from preparation 66 (200 mg, 0.46 mmol) was added aceticacid saturated with HCl(g) (10 mL, ˜3N in HCl) and the solution stirredvigorously at room temperature for 1 h. The reaction was concentrated,followed by addition of acetonitrile and concentrated to assist in theremoval of acetic acid. The resulting white solid was treated with ethylether, sonicated, and filtered to yield 159 mg of the title compound asa white solid, 93% yield. ¹H NMR: consistent with structure. MS (ionspray) 369 (M⁺).

PREPARATION 695-((1S,3R)-3-aminocyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-oneHydrochloride

To a compound from preparation 67 (368 mg, 0.85 mmol) was added aceticacid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and the solutionstirred vigorously at room temperature for 1 h. The reaction wasconcentrated, followed by addition of acetonitrile and concentrated toassist in the removal of acetic acid. The resulting white solid wastreated with ethyl ether, sonicated, and filtered to yield 249 mg of thetitle compound as a white solid, 79% yield. ¹H NMR: consistent withstructure. MS (ion spray) 369 (M⁺).

PREPARATION 70 Ethyl 4-aminohexanecarboxylate

Thionyl chloride (3.0 mL, 0.041 mol) was added dropwise to ethanol (125mL) at room temperature and the mixture stirred for an additional 10min. Then, 4-amino-1-cyclohexane-carboxylic acid (5.0 g, 0.035 mol) wasadded and the mixture stirred overnight at ambient temperature. Themixture was then concentrated in vacuo and the resulting solid driedovernight in vacuo which resulted in the isolation of 6.84 g (94%) ofthe desired ester hydrochloride. MS(S): (M+1)⁺172.2 m/z.

PREPARATION 71 Ethyl4-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexaneCarboxylate

A compound from preparation 70 (0.414 g, 0.002 mol) was combined with3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (0.548g, 0.002 mol) and triethylamine (0.70 mL, 0.005 mol) in CH₂Cl₂ (6.0 mL)and the mixture stirred for 5 h at ambient temperature. The mixture wasdiluted with CH₂Cl₂, washed with 2× water, and dried over sodiumsulfate. The mixture was concentrated in vacuo. The resulting residuechromatographed over silica gel using CH₂Cl₂/MeOH as eluant whichallowed for isolation of 0.790 g (97%) of the desired amide. MS(ES):(M⁺1)⁺409.3, 410.3, 411.2 m/z.

PREPARATION 72 Ethyl4-(9-chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexaneCarboxylate

A compound from preparation 71 (0.70 g, 0.0017 mol) was dissolved in DMF(10 mL) and potassium-t-butoxide (0.230 g, 0.0020 mol) was added and themixture stirred for 2 h at ambient temperature. Water (100 mL) and aq 1NHCl (5 mL) was added and the aqueous mixture extracted with ethylacetate. The combined extracts were dried over sodium sulfate and thenconcentrated in vacuo. The resulting residue was chromatographed oversilica gel using CH₂Cl₂/MeOH as eluant which allowed for isolation of0.540 g (81%) of product as a light yellow solid. MS(ES): (M+1)⁺ 389.2,391.2 m/z.

PREPARATION 73 3-[(t-Butoxy)carbonylamino)cyclohexanecarboxylic Acid

To 3-aminocyclohexane carboxylic acid (3.00 g, 0.021 mol) in a THF/H₂Omixture (50 mL/50 mL) was added potassium carbonate (2.90 g, 0.021 mol)and di-t-butyl dicarbonate (4.58 g, 0.021 mol) and the resultant mixturestirred overnight at ambient temperature. Then aqueous 5N HCl (10 mL)was added and the mixture extracted with ethyl acetate. The combinedextracts were dried over sodium sulfate and concentrated in vacuo whichallowed for isolation of 4.92 g (96%) of desired product as a whitesolid.

MS(ES): (M+1)⁺ 244.5 m/z.

PREPARATION 74 (t-Butoxy)-N-[3-(hydroxymethyl)cyclohexyl]carboxamide

A compound from preparation 73 (4.00 g, 0.0165 mol) was dissolved in dryTHF (50 mL) and the mixture cooled in an ice bath under a nitrogenatmosphere. Then borane-tetrahydrofuran (1.0 M, 20 mL, 0.02 mol) wasadded via syringe and the mixture stirred overnight while warming toroom temperature. The reaction mixture was quenched into ice water andsolid NaCl was added. This mixture was extracted with ethyl acetate andthe combined extracts were dried over sodium sulfate and concentrated invacuo. The resulting residue was chromatographed over silica gel using aCH₂Cl₂/THF mixture as eluant which allowed for isolation of 2.40 g (63%)of the desired alcohol as a viscous oil.

MS(ES): (+1)⁺ 230.2 m/z.

PREPARATION 75(t-Butoxy)-N-[3-p-toluenesulfonyloxymethyl)cyclohexyl]carboxamide

A compound from preparation 74 (0.15 g, 0.00066 mol) was combined withp-toluenesulfonyl chloride (0.125 g, 0.00066 mol), triethylamine (0.18mL, 0.0013 mol), and DMAP (0.005 g, cat.) in dichloromethane (5.0 mL)and the resultant mixture stirred overnight at room temperature. Themixture was then concentrated in vacuo and the residue chromatographedover silica gel using a mixture of CH₂Cl₂/THF as eluant which allowedfor the isolation of the desired product (0.195 g, 77%) as a thick oilthat solidified upon standing. MS(ES): (M+1)⁺ 384.2 m/z.

PREPARATION 76 (t-Butoxy)-N-[3-(phenylthiomethyl)cyclohexyl]carboxamnide

Thiophenol (0.27 mL, 0.0026 mol) was dissolved in DMF (10 mL) at ambienttemperature under a nitrogen atmosphere and sodium hydride (60%, 0.115g, 0.0029 mol) was added. After stirring for 15 min., a compound frompreparation 75 was added and the mixture stirred overnight at ambienttemperature. The mixture was concentrated in vacuo and the residuechromatographed over silica gel with CH₂Cl₂/THF as eluant which allowedfor isolation of 0.74 g (88%) of desired product as a white solid.MS(ES):

(M+1)⁺ 322.2 m/z.

PREPARATION 77 3-(Phenylthiomethyl)cyclohexylamine

A compound from preparation 76 (0.50 g, 0.0016 mol) was dissolved inCH₂Cl₂ (10 mL) and TFA (1.0 mL) was added. After 1.5 h, deprotection wasincomplete and additional TFA (1.0 mL) was added and the mixture stirredat ambient temperature for an additional 4 h. The mixture wasconcentrated in vacuo and the residue treated with aqueous NaHCO₃ andextracted with CH₂Cl₂. The combined extracts were concentrated in vacuoand the residue eluted over a short plug of silica gel (CH₂Cl₂/MeOH)which allowed for isolation of the desired amine (0.265 g, 77%). MS(ES):(M+1)⁺ 222.2 m/z.

PREPARATION 78[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-[3-(phenylthiomethyl)cyclohexyl]carboxamide

A compound from preparation 77 (0.26 g, 0.0012 mol) was combined with3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride(0.322 g, 0.0012 mol) and triethylamine (0.33 mL, 0.0024 mol) in CH₂Cl₂(10 mL) and the mixture stirred overnight at ambient temperature. Thereaction mixture was chromatographed over silica gel using CH₂Cl₂/THF aseluant which allowed for isolation of 0.495 g (91%) of the desired amideas a white solid. MS(ES): (+1)⁺ 459.4 m/z.

PREPARATION 79(t-Butoxy)-N-[3-(phenylmethylthiomethyl)cyclohexyl]carboxamide

Benzyl mercaptan (0.31 mL, 0.0026 mol) was dissolved in DMF (10 mL) atambient temperature under a nitrogen atmosphere and sodium hydride (60%,0.115 g, 0.0029 mol) was added. After stirring for 15 min., the compoundfrom preparation 75 (1.00 g, 0.0026 mol) was added and the mixturestirred overnight at ambient temperature. The mixture was concentratedin vacuo and the residue chromatographed over silica gel with CH₂Cl₂/THFas eluant which allowed for isolation of 0.80 g (92%) of desired productas a thick oil which solidified upon standing. MS(ES): (M+1)⁺ 336.2 m/z.

PREPARATION 80[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-[3-(phenylmethylthiomethyl)cyclohexyl]carboxamide

The compound from preparation 73 (0.40 g, 0.0012 mol) was dissolved inCH₂Cl₂ (8.0 mL) and TFA (2.0 mL) and the mixture stirred at ambienttemperature for 3 h. The mixture was concentrated in vacuo and theresidue treated with aqueous NaHCO₃ and extracted with CH₂Cl₂. Thecombined extracts were dried over sodium sulfate and concentrated invacuo which allowed for the recovery of 0.19 g (68%) of crude amine.This amine (0.19 g, 0.0008 mol) was combined with3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride(0.22 g, 0.0008 mol) and triethylamine (0.23 mL, 0.0016 mol) in CH₂Cl₂(10 mL) and the mixture stirred overnight at ambient temperature. Water(˜30 mL) was added and the mixture extracted with CH₂Cl₂. The combinedextracts were dried over sodium sulfate and then concentrated in vacuo.The resulting residue was chromatographed over silica gel usingCH₂Cl₂/THF as eluant which allowed for isolation of 0.29 g (77%) of thedesired amide as a white solid. MS(ES): (M+1)⁺ 473.1, 475.1 m/z.

PREPARATION 81(t-Butoxy)-N-[3-{(benzylsulfonyl)methyl}cyclohexyl]carboxamide

A compound from preparation 79 (0.467 g, 0.0014 mol) was dissolved in amethanol/acetone (10 mL)/(10 mL) mixture and NaHCO₃ (0.467 g, 0.0056mol) and water (10 mL) were added. Oxone® (1.71 g, 0.0028 mol) was thenadded and the mixture stirred at ambient temperature for 2.5 h. Themixture was concentrated i71 vacuo and the residue taken up in water andextracted with CH₂Cl₂. The combined extracts were dried over sodiumsulfate and concentrated in vacuo. The resulting residue waschromatographed over silica gel using CH₂Cl₂/THF as eluant which allowedfor isolation of 0.420 g (82%) of the desired sulfone as a white solid.MS(FD): M⁺ 367.2 m/z.

PREPARATION 82[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-(3-{benzylsulfonyl]methyl}cyclohexyl)carboxamide

The compound from preparation 81 (0.40 g, 0.0011 mol) and TFA (2.0 mL)were dissolved in CH₂Cl₂ (10.0 mL) and the mixture stirred at ambienttemperature for 2 h. The mixture was concentrated in vacuo and theresidue treated with aqueous NaHCO₃ and extracted with CH₂Cl₂. Thecombined extracts were dried over sodium sulfate and concentrated invacuo which allowed for recovery of 0.21 g (71%) of crude amine. Thisamine (0.21 g, 0.0008 mol) was combined with3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride(0.22 g, 0.0008 mol), triethylamine (0.22 mL, 0.0016 mol) and DMAP(0.005 g, cat.) in CH₂Cl₂ (10 mL) and the mixture stirred overnight atambient temperature. The mixture was concentrated in vacuo and theresulting residue chromatographed over silica gel using CH₂Cl₂/THF aseluant which allowed for isolation of 0.35 g (89%) of the desired amide.MS(ES): (M+1)⁺ 505.1 m/z.

PREPARATION 83 {3-[(t-Butoxy)carbonylamino]cyclohexyl}methyl Benzoate

The compound from preparation 74 (1.00 g, 0.0044 mol) was combined withbenzoyl chloride (0.56 mL, 0.0048 mol), triethylamine (1.70 mL, 0.012mol), and DMAP (0.020 g, cat.) in CH₂Cl₂ (10 mL) and the mixture stirredovernight at ambient temperature. The reaction mixture was concentratedin vacuo and the residue chromatographed over silica gel usingCH₂Cl₂/THF as eluant which allowed for isolation of 1.05 g (72%) of thedesired ester as an oil. MS(ES): (M+1)⁺ 334.1 m/z.

PREPARATION 84(3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)methylBenzoate

The compound from preparation 83 (1.00 g, 0.003 mol) and TFA (2.0 mL)were dissolved in CH₂Cl₂ (10 mL) and the mixture treated in a mannersimilar to preparation 82, which allowed for isolation of 0.69 g (98%)of crude amine. This amine (0.69 g, 0.0029 mol) was combined with3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (0.81g, 0.0029 mol) and triethylamine (0.82 mL, 0.0059 mol) in CH₂Cl₂ (10 mL)and again treated in a manner similar to preparation 81. Purificationresulted in the recovery of 1.30 g (95%) of desired amide as a whitefoam. MS(ES): (M+1)⁺ 471.1 m/z.

PREPARATION 859-Chloro-5-[3-(hydroxymethyl)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one

The compound from Example 489 (0.33 g, 0.00073 mol) was added to aqueoussodium hydroxide (1N, 1.0 mL), ethanol (2.0 mL) and THF (2.0 mL) and themixture stirred at ambient temperature for 3 h. The mixture was dilutedwith water and extracted with ethyl acetate. The combined extracts werewashed with 2× sat'd aq NaHCO₃ and dried over sodium sulfate.Concentration in vacuo netted 0.225 g (88%) of desired alcohol as a tanfoam. MS(ES): 347.2, 349.3 m/z.

PREPARATION 86 2-{3-[(t-Butoxy)carbonylamino]cyclohexyl}acetic Acid

A compound from preparation 45 (1.0 g; 2.77 mmol) was dissolved intetrahydrofuran (4 mL) and ethanol (4 mL) under a dry nitrogenatmosphere at room temperature. This cloudy white solution became clearand colorless after mixing with 2N NaOH_((aq)) (15 mL; 19.4 mmol; 11.1equiv) for 2 h. After rotary evaporation to dryness, the white solid wasdissolved in water (20 mL) and the resulting solution extracted withdiethyl ether (twice). Acidification of the aqueous layer to pH 2 with1N HCl_((aq)) produced a white solid that was extracted into ethylacetate (thrice). The ethyl acetate was washed with saturatedNaCl_((aq)), dried with Na₂SO_(4(s)), and concentrated to dryness byrotary evaporation. The resulting white solid (700 mg; 98% yield) wasused in subsequent reactions without further purification. MS(ES)calc'd: [M+Na]⁺ 280.2 m/z, [M−H]⁻=256.2 m/z. Found: 280.1 m/z; 256.2m/z.

PREPARATION 872-{3-[(t-Butoxy)carbonylamino]cyclohexyl}-N-ethoxy-N-methyl Acetamide

A compound from preparation 86 (690 mg; 2.68 mmol) was dissolved inanhydrous dichloromethane (10 mL) under a dry nitrogen atmosphere atroom temperature. Addition of 1,1′-carbonyldiimidazole (535 mg; 3.22mmol; 1.2 equiv) to the clear, colorless starting material solutionimmediately generated a gas. After stirring the resulting solution for30 min, triethyl amine (746 μL; 5.36 mmol; 2 equiv) andN,O-dimethylhydroxylamine hydrochloride (570 mg; 5.90 mmol; 2.2. equiv)were added and the solution stirred for 15 h. Water was added to thesolution and then the solution was extracted with dichloromethane(thrice). The organic layer was washed with saturated NaCl_((aq)), driedwith Na₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The resulting oil (850 mg) was purified by radialchromatography on a 4 mm thick silica gel rotor with a 5%tetrahydrofuran/dichloromethane (v/v) mobile phase. A clear, colorlessoil (650 mg; 80%) was obtained. MS(ES) calc'd: [M+Na]⁺=323.2 m/z. Found:323.2 m/z.

PREPARATION 88(t-Butoxy)-N-[3-(2-oxo-3-phenylpropyl)cyclohexyl]carboxamide

A compound from preparation 87 (4.11 g; 13.7 mmol) was dissolved inanhydrous tetrahydrofuran (100 mL) under a dry nitrogen atmosphere. Theclear, colorless solution became clear and brown upon addition of 0.5 Mbenzylmagnesium chloride in tetrahydrofuran (15 mL; 30.1 mmol; 2.2equiv). The reaction was quenched with water (100 mL) after 0.5 h andthe product was extracted from the quenched solution with ethyl acetate.The organic layer was washed with saturated NaCl_((aq)) (once), driedwith Na₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The resulting oil was purified by silica gel chromatographyon a 6×15 cm column with a 2% acetonitrile/dichloromethane (v/v) mobilephase. A white solid (3.17 g; 70%) was obtained after concentration ofappropriate fractions. TOF-MS(ES) calc'd: [M+Na]⁺=354.2045 m/z.

Found: 354.2037 m/z.

PREPARATION 89[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-[3-(2-oxo-3-phenylpropyl)cyclohexyl]carboxamide

A compound from preparation 88 (3.0 g; 9.05 mmol) was dissolved inexcess, neat acetic acid saturated with HCl_((g)) (20 mL). After 30 minof stirring at room temperature, in air, the solution was concentratedto dryness by rotary evaporation. Acetic acid was removed from theresultant solid by consecutive dissolution in, and drying from,acetonitrile (thrice) and then diethyl ether (once). The resulting whitepowder was dissolved in anhydrous dichloromethane (400 mL) under anitrogen atmosphere. First was added3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (2.74g; 9.99 mmol; 1.1 equiv), and then 4-N,N-dimethylaminopyridine (114 mg;0.93 mmol; 0.1 equiv) and finally triethylamine (5 mL; 36.3 mmol; 4equiv). The reaction solution was stirred 17 h and then quenched withsaturated NaHCO_(3(aq)). The organic layer was washed with saturatedNaHCO_(3(aq)) (twice), saturated NaCl_((aq)) (once), dried withNa₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The resulting oil was dissolved in dichloromethane andpurified by column chromatography on a 6×15 cm silica gel bed indichloromethane. Dichloromethane (1 L) was followed by a 2%tetrahydrofuran/dichloromethane (v/v) mobile phase. A white solid (3.93g; 95%) was obtained. TOF-MS(ES) calc'd: [M+H]⁺=469.1694 m/z. Found:469.1692 m/z.

PREPARATION 90 2-{3-[(t-Butoxy)carbonylamino]cyclohexyl}acetic Acid

A compound from preparation 87 (845 mg; 2.81 mmol) was dissolved inanhydrous tetrahydrofuran (30 mL) under a dry nitrogen atmosphere. A 1 Msolution of DIBAL-H in toluene (6.2 mL; 6.18 mmol; 2.2 equiv) was addeddropwise to the −78° C. starting material solution over 5 min. After anadditional 15 min of stirring, water quenched the cold reactionsolution. Extraction with ethyl acetate produced an emulsion that wasdestroyed by concentration of the solution to near dryness. Theresulting material was dissolved in water/diethyl ether and extractedwith diethyl ether without further complication. The organic layer waswashed with saturated NaCl_((aq)) (once), dried with Na₂SO_(4(s)),filtered, and concentrated to dryness by rotary evaporation. The productwas purified by radial chromatography on a 4 mm thick silica gel rotorwith 300 mL of 1% tetrahydrofuran/dichloromethane (v/v) mobile phasefollowed by 300 mL of 10% tetrahydrofuran/dichloromethane (v/v) mobilephase. A white solid (535 mg; 79%) was obtained after concentration ofthe desired fractions. MS(ES) calc'd: [M+H]⁺=264.1 m/z, [M−Boc+H]⁺=142.1m/z. Found: 264.1 m/z; 142.1 m/z.

PREPARATION 91N-{(1S,3S)-3-[2-(Phenylamino)ethyl]cyclohexyl}(t-butoxy)carboxamide

A nitrogen sparged round bottom flask was charged with denatured ethanol(5 mL), Ti(i-PrO)₄ (337 μL; 1.14 mmol; 2.2 equiv), and aniline (95 μL;1.04 mmol; 2 equiv). A compound from preparation 90 (125 mg; 0.518 mmol;1 equiv) was then added to the clear, colorless reaction solution. Thereaction solution became cloudy and then progressed to clear and lightyellow over 3.3 h. NaBH₄ (30 mg; 0.793 mmol; 1.5 equiv) was then addedand allowed to react overnight at room temperature. The clear, colorlessreaction solution was quenched with 2 M NH_(3(aq)) (20 mL). After afailed attempt at Celite® filtration, the product and Celite® mixturewere suspended in water and extracted with CHCl₃ (thrice). This organiclayer was washed with saturated NaCl_((aq)) (once), dried withNa₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The aqueous layer was decanted from the Celite® and theCelite® was suspended in 2 M NH_(3(aq)) (120 mL). This suspension wasextracted with CHCl₃ (trice) and the organic layer was treated similarlyto the first organic layer. The combined extracts were purified byradial chromatography on a 2 mm thick silica gel rotor. The firstchromatography with a 2% tetrahydrofuran/dichloromethane (v/v) mobilephase did not completely purify the product and was followed by a secondand third radial chromatography with a 1%tetrahydrofuran/dichloromethane (v/v) mobile phase. A white solid (55mg; 33%) was obtained after concentration of the desired fractions.MS(ES) calc'd: [M+H]⁺=319.2 m/z; [M+C₂H₃O₂]⁻=317.2 m/z. Found: 319.2m/z; 377.2 m/z.

PREPARATION 92N-{(1S,3S)-3-[2-(Phenylamino)ethyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

A compound from preparation 91 (53 mg; 0.166 mmol) was dissolved inexcess, neat acetic acid saturated with HCl_((g)) (2 mL). After 30 minof stirring at room temperature, in air, the solution was concentratedto dryness by rotary evaporation. Acetic acid was removed from theresultant solid by consecutive dissolution in, and drying from,acetonitrile (thrice) and then diethyl ether (twice). The resultingwhite powder was dissolved in anhydrous dichloromethane (8 mL) under anitrogen atmosphere. First was added3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (50.2mg; 0.183 mmol; 1.1 equiv), and then 4-N,N-dimethylaminopyridine (2 mg;0.017 mmol; 0.1 equiv) and finally triethylamine (94 μL; 0.667 mmol; 4equiv). The reaction solution was stirred overnight, then quenched withsaturated NaHCO_(3(aq)), then extracted with dichloromethane (twice).The organic layer was washed with saturated NaCl_((aq)) (once), driedwith Na₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The resulting product was dissolved in dichloromethane andpurified by radial chromatography on a 2 mm thick silica gel rotor. Adichloromethane mobile phase was followed by a 5%tetrahydrofuran/dichloromethane (v/v) mobile phase. An off-white solid(66 mg; 87%) was obtained. TOF-MS(ES) calc'd: [M+H]⁺=456.1854 m/z.

Found: 456.1850 m/z.

PREPARATION 93 Methyl2-(3-{[4-(2-chloro-6-fluorophenyl)-2-methyl-3-furyl]carbonylamino)}cyclohexyl)-acetate

Part a: To a solution containing 15.0 g (83 mmol) of m-nitrophenylaceticacid in 200 mL ethanol was added 7.5 g 5% rhodium on carbon. Thereaction was subjected to hydrogenation (60 psi) at 60° C. for 10 hours,after which the catalyst was removed by vacuum filtration and thesolvent removed in vacuo, yielding 3.5 g (27%) of an oil. This materialwas used without further purification.

Part b: 1 mL acetyl chloride was added to 30 mL methanol. To thissolution was added 3.5 g (22.3 mmol) of a compound from part a and thereaction was stirred for 1 hour. Solvents were removed in vacuo,yielding 3.24 g (70%) of an oil. This material was used without furtherpurification.

Part c: To a solution of 1.05 g (5.06 mmol) of a compound from part b in10 mL of methylene chloride was added 1.53 g (5.57 mmol) of3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride,followed by 2.11 mL (15.2 mmol) of triethylamine at room temperature.The reaction was stirred overnight, then concentrated in vacuo. Thecrude solid was dissolved in 150 mL ethyl acetate, washed 3× with 1NHCl, 3× with NaHCO₃, 3× with brine, dried over sodium sulfate andconcentrated iii vacuo yielding 1.8 g (87%) of a white solid. Thismaterial was an inseparable mixture of cis and trains isomers. MS(FIA)m/z=409.3

Part d: To a solution of 1.78 g (4.35 mmol) of a compound from part c in10 mL of DMF at room temperature was added 5 mL of 2N NaOH in MeOH. Thereaction was stirred for 1 hour and 0.537 g (4.78 mmol) of potassiumt-butoxide was added. The resulting dark red reaction was stirred for 6hours. The reaction was then added to 50 mL of 1N HCl and diluted with150 mL of ethyl acetate. The organic layer was separated and washed 3×with brine, dried over sodium sulfate and concentrated in vacuo. Thiscrude material was purified by flash chromatography, eluting with 5%MeOH(CH₂Cl₂. The major fractions were combined and concentrated in vacuoto give 1.15 g (71%) of a clear oil, which was characterized as thetitle compound. MS(FIA) m/z=375.2

PREPARATION 942-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]aceticAcid

To a solution of 1.78 g (4.35 mmol) of a product of preparation 93, in10 mL of DMF at room temperature was added 5 mL of 2N NaOH in MeOH. Thereaction was stirred for 1 h and 0.537 g (4.78 mmol) of potassiumt-butoxide was added. The resulting dark red reaction was stirred for 6h. The reaction was then added to 50 mL of 1N HCl and diluted with 150mL of ethyl acetate. The organic layer was separated and washed 3× withbrine, dried over sodium sulfate and concentrated in vacuo. This crudematerial was purified by flash chromatography, eluting with 5%MeOH/CH₂Cl₂. The major fractions were combined and concentrated in vacuoto give 1.15 g (71%) of a clear oil, which was characterized as thetitle compound. MS(FIA) m/z=375.2.

PREPARATION 952-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]acetylChloride

To an ice bath cooled solution containing 0.75 g (2.0 mmol) a compoundfrom preparation 94 in 10 mL methylene chloride and catalytic DMF (3drops) was added 0.262 mL (3.0 mmol) of oxalyl chloride in one portion.The ice bath was removed and the reaction stirred for 3 h. The solventswere removed in vacuo and the resulting oil azeotroped with toluene.This material was characterized as the title compound and used withoutfurther purification.

PREPARATION 96 Methyl 3-(azidomethyl)benzoate

To a solution of methyl 3-(bromomethyl)benzoate in DMF (55 ml) under N₂was added sodium azide (10.39 g, 160 mmol) and stirred for 3 h. Thesolution was diluted with EtOAc, washed (water twice, then brine), dried(MgSO₄), filtered, and concentrated to give the title compound. Thismaterial was used without further purification. MS (EI+) (m/z)=101.1[M⁺+1]

PREPARATION 97 Methyl 3-{[(t-butoxy)carbonylaminomethyl}benzoate

A mixture of a compound from preparation 95 (8.75 g, 45.8 mmol), (BOC)₂O(11.98 g, 55 mmol), 10% Pd/C catalyst (4.76 g), and EtOAc (175 mL) wasstirred under an atmosphere of hydrogen gas (balloon) for 18 h, filteredthrough celite, and concentrated. Column chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (5.8 g, 48%). MassSpectrum (ES+) (m/z) 166.0 [M-BOC].

PREPARATION 98 Methyl 3-{[(t-butoxy)carbonylamino]methyl}cyclohexaneCarboxylate

A mixture of a compound from preparation 97 (5.57 g, 20 mmol), 5% Rh/C(2.78 g), and MeOH (140 mL) was shaken in a PARR apparatus at 60 psi and60° C. for 18 h, filtered through celite, and concentrated. Columnchromatography (silica gel, hexanes/EtOAc gradient) gave the titlecompound (3.5 g, 62%). Mass Spectrum (ES+) (m/z) 166.0 [M-BOC].

PREPARATION 99 Methyl3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-5-yl]carbonylamino}cyclohexaneCarboxylate

To a solution of a compound from preparation 98 (0.5 g, 1.845 mmol) indichloromethane (10 mL) was added TFA (7 mL) and stirred for 45 min. Thesolution was concentrated using benzene to azeotrope. The residue wasdissolved in dichloromethane (20 mL) and Et₃N (0.77 mL, 5.54 mmol) and3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (0.56g, 2.03 mmol) were added under N₂. The solution was stirred overnight.The reaction was diluted with EtOAc, washed (0.1N HCl, H₂O, and brine),dried (MgSO₄), filtered, and concentrated. Column chromatography (silicagel, hexanes/EtOAc gradient) gave the title compound (0.52 g, 69%). MassSpectrum (FIA) (m/z) 409.3 [M+1].

PREPARATION 100 Methyl3(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin-5-yl)cyclohexaneCarboxylate

A compound from preparation 99 (0.445 g, 1.09 mmol) and t-BuOK (0.135 g,1.2 mmol), in DMF (15 mL) were allowed to react for 15 min under N₂. Icewater was added and extracted twice with EtOAc. The combined EtOAclayers were washed, dried, filtered, and concentrated. Columnchromatography (silica gel, hexanes/EtOAc gradient) gave the titlecompound (0.329 g, 78%). Mass Spectrum (FIA) (m/z) 389.2 [M+1].

PREPARATION 101 Methyl3(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexaneCarboxylate

A compound from preparation 100 (5.17 g, 12.7 mmol) and t-BuOK (1.56 g,13.97 mmol), in DMF (130 mL) were allowed to react for 20 min under N₂.Ice water was added and extracted twice with EtOAc. The combined EtOAclayers were washed, dried, filtered, and concentrated. Columnchromatography (silica gel, acetone/dichloromethane gradient) gave cis(0.28 g, 7%), trans (1.08 g, 25%), and unseparated title compound (2.91g, 68%).

Mass Spectrum (FIA) (m/z) 389.2 [M+1].

Mass Spectrum (FIA) (m/z) 389.2 [M+1].

PREPARATION 1023-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexaneCarboxylate Racemic

A cis compound from preparation 101 (1.08 g, 2.78 mmol), 1N NaOH (7 mL,6.94 mmol), MeOH (20 mL), and THF (20 mL) were allowed to react for 5 hat 50° C. The reaction was cooled to room temperature, diluted withwater, and acidified (conc. HCl) to less than pH 3. The mixture wasextracted with EtOAc (2×) and the combined extracts were washed, dried,filtered, and concentrated to give the title compound (1.03 g, 98%).

Mass Spectrum (ES+) (m/z) 375.1 [M+1].

PREPARATION 103 2-{3-[(t-Butoxy)carbonylamino]cyclohexyl}acetic Acid

To a solution of a compound from preparation 45 (5.0 g, 14.4 mmol),dioxane (96 ml), and 1.0 N NaOH (28.8 ml, 28.8 mmol) was heated at 50°C. for 3 h. The reaction was cooled to room temperature, diluted withH₂O, and extracted with Et₂O. The aqueous layer was acidified (conc.HCl) to less than pH 3, and extracted with EtOAc (2×). The combinedextracts were washed (brine), dried (MgSO₄), filtered, and concentratedto give the title compound.

PREPARATION 104N-((1S,3R)-3-{[(Phenylmethoxy)carbonylamino]methyl}cyclohexyl)(t-butoxy)carboxamide

To a solution of a compound from preparation 103 (3.43 g, 13.35 mmol),Et₃N (3.75 mL, 26.96 mmol) in toluene (86 mL) under N₂ was added DPPA(5.8 mL, 26.96 mmol) and benzyl alcohol (4.28 mL, 41.38 mmol). Thesolution was heated to reflux overnight. The reaction was cooled to roomtemperature, diluted with EtOAc, washed (1.0N NaOH then brine), dried(MgSO₄), filtered, and concentrated. Column chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (3.05 g, 63%). MassSpectrum (ES+) (m/z) 263.1 [M−BOC].

PREPARATION 105N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}(t-butoxy)carboxamide

A mixture of a compound from preparation 104 (0.25 g, 0.69 mmol),benzoic anhydride (0.187 g, 0.828 mmol), 10% Pd/C catalyst (0.1 g), andEtOAc (10 mL) was stirred under an atmosphere of hydrogen gas (balloon)for 17 h. Added more benzoic anhydride (0.187 g, 0.828 mmol), and DMAP(0.025 g, 0.23 mmol), stirred for 2.5 h, filtered through celite, andconcentrated. Column chromatography (silica gel, hexanes/EtOAc gradient)gave the title compound (0.208 g, 91%). Mass Spectrum (FIA) (m/z) 333.2[M+1].

PREPARATION 106N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

In a fashion similar to that described for preparation 46, a compoundfrom preparation 105 (0.1 g, 0.3 mmol), TFA (2.5 mL), dichloromethane (4mL), 3-(2,6-difluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (0.13g, 0.5 mmol), and Et₃N (0.125 mL, 0.9 mmol) gave the title compound(0.109 g, 80%) after column chromatography (silica gel, hexanes/EtOAcgradient). Mass Spectrum (ES+) (m/z) 454.2 [M+1].

PREPARATION 107N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-phenylisoxazol-4-yl]carboxamide

In a fashion similar to that described for preparation 46, a compoundfrom preparation 103 (0.1 g, 0.3 mmol), TFA (2.5 mL), dichloromethane (4mL), 3-(2-chloro-6-fluoro-phenyl)-5-phenyl-isoxazole-4-carbonyl chloride(0.15 g, 0.45 mmol), and Et₃N (0.125 mL, 0.9 mmol) gave the titlecompound (0.14 g, 88%) after column chromatography (silica gel,acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 532.1[M+1].

PREPARATION 108N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[5-2-fluorophenyl)(1,3-oxazol-4-yl)]carboxamide

A solution of a compound from preparation 105 (0.1 g, 0.3 mmol) in TFA(2 mL) was stirred for 1.5 h. The solution was concentrated usingbenzene to azeotrope, diluted with EtOAc, washed (1.0N NaOH), dried(Na₂SO₄), filtered, and concentrated. The residue was dissolved indichloromethane (1.5 mL) and added to a mixture of EDCI (0.086 g, 0.45mmol), DMAP (0.007 g, 0.06 mmol),5-(2-fluoro-phenyl)-oxazole-4-carboxylic acid (0.087 g, 0.36 mmol) indichloromethane (1.5 mL) under N₂. The reaction was stirred for 65 h,diluted with dichloromethane, washed (1.0N HCl, 2.0N NaOH, H₂O, andbrine), dried (MgSO₄), filtered, and concentrated. Column chromatography(silica gel, acetone/dichloromethane gradient) gave the title compound(0.111 g, 81%). Mass Spectrum (FIA) (m/z) 456.2 [M+1].

PREPARATION 109N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2-fluoro-3-iodophenyl)-5-methylisoxazol-4-yl]carboxamide

In a fashion similar to that described for preparation 108, a compoundfrom preparation 105(0.1 g, 0.3 mmol), TFA (2 mL), dichloro-methane (1.5mL), EDCI (0.086 g, 0.45 mmol), DMAP (0.007 g, 0.06 mmol),3-(2-fluoro-3-iodo-phenyl)-5-methyl-isoxazole-4-carboxylic acid (0.125g, 0.36 mmol), and dichloromethane (1.5 mL) gave the title compound(0.104 g, 62%) after column chromatography (silica gel,acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 562.1[M+1].

PREPARATION 110N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2-fluoro-3-iodophenyl)-5-iodophenyl-4-yl]carboxamide

In a fashion similar to that described for preparation 108, a compoundfrom preparation 105 (0.1 g, 0.3 mmol), TFA (2 mL), dichloro-methane(1.5 mL), EDCI (0.125 g, 0.45 mmol), DMAP (0.007 g, 0.06 mmol),3-(2-fluoro-5-iodo-phenyl)-5-methyl-isoxazole-4-carboxylic acid (0.125g, 0.36 mmol), and dichloromethane (1.5 mL) gave the title compound(0.088 g, 53%) after column chromatography (silica gel,acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 562.1[M+1].

PREPARATION 111N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2,4-difluorophenyl)-5-methylisoxazol-4-yl]carboxamide

In a fashion similar to that described for preparation 108, a compoundfrom preparation 105 (0.1 g, 0.3 mmol), TFA (2 mL), dichloromethane (1.5mL), EDCI (0.086 g, 0.45 mmol), DMAP (0.007 g, 0.06 mmol),3-(2,4-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid (0.086 g,0.36 mmol), and dichloromethane (1.5 mL) gave the title compound (0.123g, 90%) after column chromatography (silica gel, acetone/dichloromethanegradient). Mass Spectrum (FIA) (m/z) 454.2 [M+1].

PREPARATION 112N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-hexylisoxazol-4-yl]carboxamide

In a fashion similar to that described for preparation 108, a compoundfrom preparation 105 (0.1 g, 0.3 mmol), TFA (2 mL), dichloromethane (1.5mL), EDCI (0.086 g, 0.45 mmol), DMAP (0.007 g, 0.06 mmol),3-(2-chloro-6-fluoro-phenyl)-5-hexyl-isoxazole-4-carboxylic acid (0.117g, 0.36 mmol), and dichloromethane (1.5 mL) gave the title compound(0.112 g, 69%) after column chromatography (silica gel,acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 540.5[M+1].

PREPARATION 113 Phenylmethyl2-((3S,1R)-3-{[5-methyl-3-(6-fluoro-2-iodophenyl)isoxazol-4-yl]carbonylamino}cyclohexyl)acetate

In a fashion similar to that described for preparation 99, a compoundfrom preparation 45 (5.1 g, 14.7 mmol), dichloromethane (30 mL), TFA (30mL), dichloromethane (150 mL),3-(2-fluoro-6-iodo-phenyl)-5-methylisoxazole-4-carboxylic acid (6.39 g,17.49 mmol), and Et₃N (6.03 mL, 43.4 mmol) gave the title compound (7.15g, 86%) after column chromatography (silica gel, hexanes/EtOAcgradient). Mass Spectrum (ES+) (m/z) 577.0 [M+1].

PREPARATION 114 Phenylmethyl2-[(3S,1R)-3-(9-iodo-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]acetate

A compound from Example 499 (1.87 g, 3.35 mmol), 1.0N NaOH (6.7 mL, 6.7mmol), and dioxane (20 mL) were allowed to react for 2 h at 50° C. in afashion similar to that of preparation 29 to give the title compound(1.57 g, 100%). Mass Spectrum (ES+) (m/z) 467.0 [M+1].

PREPARATION 115 N-({(3S,1R)-3-aminocyclohexyl}methyl)benzamide

A solution of a compound from preparation 105 (5.3 g, 15.96 mmol) in TFA(50 mL) was stirred for 2 h. The reaction was concentrated using benzeneazeotrope, diluted with EtOAc, washed (1.0N NaOH), dried (Na₂SO₄),filtered, and concentrated to give the title compound (3.41 g, 92%).Mass Spectrum (ES+) (m/z) 233.1 [M+1].

PREPARATION 116N-[(1S,3S)-3-(3-oxo-3-phenylpropyl)cyclohexyl][5-methyl-3-(6-fluoro-2-iodophenyl)isoxazol-4-yl]carboxamide

To a solution of a compound from preparation 115 (3.4 g, 14.7 mmol),Et₃N (6.14 mL, 44.1 mmol) in dichloromethane (150 mL) was added3-(2-fluoro-6-iodo-phenyl)-5-methylisoxazole-4-carboxylic acid (6.97 g,19.4 mmol) under N₂ and stirred for 4 h. The reaction was diluted withdichloromethane, washed (0.1N HCl then brine), dried (MgSO₄), filtered,and concentrated. Column chromatography (silica gel,acetone/dichloromethane gradient) gave the title compound (4.89 g, 59%).Mass Spectrum (ES+) (m/z) 562.0 [M+1].

PREPARATION 117 4-Amino-1-ethylcyclohexanecarboxylate Hydrochloride

Thionyl chloride (2.55 mL, 35 mmol) was added dropwise to absoluteethanol (100 mL) under a N₂ atmosphere. The resulting solution wasstirred at room temperature for 10 min then4-amino-1-cyclohexanecarboxylic acid (4.29 g, 30 mmol, cis, transmixture) was added as a solid. The resulting solution was stirred atroom temperature overnight. The solvent was removed in vacuo, theresidue dissolved in ethanol (25 mL) and this solution was slowly addedto a flask containing rapidly stirred ether (700 mL). The precipitatethat formed was collected by filtration and dried in vacuo to give 5.75g, 92% as a white solid. MS (ion spray) 172 (M+1).

PREPARATION 118 Ethyl4-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexanecarboxylate

To a solution of a compound from preparation 117 (1.04 g, 5 mmol) inmethylene chloride (15 mL) was added triethyl amine (0.8 mL, 5.7 mmol)followed by 3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonylchloride (1.37 g, 5 mmol) in methylene chloride (10 mL), and anadditional aliquot of triethyl amine (0.75 mL, 5.3 mmol). After aninitial exotherm the mixture was stirred at room temperature for 4 h.The mixture was diluted with methylene chloride, washed with water, 1Naqueous hydrochloric acid solution, and brine, dried (MgSO₄), filtered,and concentrated in vacuo. The residue was purified by flashchromatography, eluting with 4:1 toluene: ethyl acetate, to give 2.0 g98% of the title compound as a white solid. ¹H—NMR was consistent withthe desired structure. MS (ion spray) 409.3 (M+1).

PREPARATION 119 Ethyl4-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin-5-yl)cyclohexanecarboxylate

To a room temperature solution of a compound from preparation 118 (1.75g, 4.28 mmol) in anhydrous DMF (20 mL) was added potassium t-butoxide(560 mg, 5 mmol). The resulting solution was stirred for 50 min, atwhich time TLC (1:1 hexane:ethyl acetate) showed the starting materialhad been consumed. The addition of 1N hydrochloric acid solution (5 mL)and water (95 mL) quenched the reaction. The mixture was extracted withethyl acetate, the extracts were washed with water, and brine, dried(MgSO₄), filtered, and concentrated in vacuo. The residue was purifiedby flash chromatography, eluting with 9:1 methylene chloride: THF, togive 1.43 g 85% of the title compound, approximately 2:1 mixture ofdiastereoisomers, as a yellow tinted solid. ¹H—NMR was consistent withthe desired structure. MS (ion spray) 389 (M+1).

PREPARATION 1204-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanecarboxylic Acid

To a solution of a compound from preparation 119 (390 mg, 1 mmol) in THF(7 mL) was added 0.5 M LiOH solution (5 mL). The mixture was stirred atroom temperature for 3 days then acidified with of 0.1N hydrochloricacid solution (5 mL) and extracted with ethyl acetate. The extracts werewashed with brine, dried (MgSO₄), filtered, and concentrated in vacuo togive 370 mg of the title compound as a yellow foam. NMR was consistentwith the desired product.

PREPARATION 121 (3-Aminocyclohexyl)(phenylsulfonyl)amine

A solution of 1,3-diaminocyclohexane (1.14 g, 10 mmol, undeterminedisomer mixture) in methylene chloride (50 mL) was cooled to 0° C. andphenylsulfonyl chloride (0.64 mL, 5 mmol) was added dropwise. Themixture was stirred at 0° C. for 4 h, then 1N sodium hydroxide solution(10 mL) was added and the mixture stirred an additional 5 min. Thephases were separated, the organic phase was dried (K₂CO₃), filtered,and concentrated in vacuo. Toluene was added and the mixturere-concentrated to remove any remaining diamine, to give 0.77 g of asemi solid. ¹H—NMR was consistent with the desired structure. MS (ionspray) 255 (M+1).

PREPARATION 122[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-{3-[(phenylsulfonyl)amino]cyclohexyl}carboxamide

To a solution of a compound from preparation 121 (750 mg, 2.95 mmoltheoretical) in methylene chloride (30 mL) was added triethylamine (0.6mL, 4.3 mmol) followed by3-(2-chloro-6-fluoro-phenyl)5-methylisoxazole-4-carbonyl chloride (822mg, 3 mmol). The resulting mixture was stirred at room temperature for 3h. The mixture was diluted with ethyl acetate, washed with 1Nhydrochloric acid solution, saturated aqueous sodium bicarbonatesolution, brine, then dried (MgSO₄), filtered, and concentrated invacuo. Radial chromatography eluting with 95:5 methylene chloride: THFgave the less polar cis isomer (780 mg), mixed fractions (130 mg), andthe more polar trans isomer (410 mg). The cis isomer: ¹H—NMR wasconsistent with the desired structure, plus a small amount of thebis-sulfonylated diamine. MS (ion spray) 492 (M+1). For the transisomer: 1H—NMR was consistent with the desired structure. MS (ion spray)492 (M+1).

PREPARATION 123 2-{(3S, 1R)-3-[(t-Butoxy)carbonylamino]cyclohexyl}aceticAcid

A compound from preparation 45 (3.30 g, 0.0095 mol) was combined withaqueous 2N sodium hydroxide (35 mL), tetrahydrofuran (10 mL), andethanol (10 mL) and the mixture stirred at room temperature for 2 h. Themixture was then concentrated in vacuo to remove volatile organics andadditional water was added to the aqueous mixture. This basic aqueousmixture was then extracted with diethylether followed by carefulacidification using 1N HCl. The acidic aqueous mixture was thenextracted with ethyl acetate. The combined ethyl acetate extracts weredried over sodium sulfate followed by concentration in vacuo whichprovided the title compound (2.40 g, 98%) as a white solid. MS(ES):(M−1)⁻ 256.2 m/z.

PREPARATION 124 N-[(1S,3R)-3-(2-Hydroxyethyl)cyclohexyl](t-butoxy)Carboxamide

The compound from preparation 123 (2.10 g, 0.0082 mol) was dissolved indry THF (35 mL) and the mixture cooled in an ice bath under a nitrogenatmosphere. Then borane-tetrahydrofuran (1.0 M, 12.25 mL, 0.0122 mol)was added via syringe and the mixture stirred overnight while slowlywarming to room temperature. The reaction mixture was quenched into icewater and solid NaCl was added. This mixture was extracted with ethylacetate and the combined extracts were dried over sodium sulfate andconcentrated in vacuo. The resulting residue was chromatographed oversilica gel using a CH₂Cl₂/THF mixture as eluant which allowed forisolation of 1.35 g (67%) of the desired alcohol. MS(ES): (M+1)⁺ 244.5m/z.

PREPARATION 125N-[(1S,3R)-3-(2-p-toluenesulfonylethyl)cyclohexyl](t-butoxy)carboxamide

The compound from preparation 124 (1.30 g, 0.0054 mol) was combined withp-toluenesulfonyl chloride (1.12 g, 0.0059 mol), triethylamine (1.49 mL,0.011 mol) and DMAP (0.02 g, cat.) in dichloromethane (30 mL) and theresultant mixture stirred overnight at room temperature. The mixture wasthen concentrated in vacuo and the residue chromatographed over silicagel using a mixture of CH₂Cl₂/THF as eluant which allowed for theisolation of the desired product (1.92 g, 90%). MS(ES): (M+1)⁺ 398.2m/z.

PREPARATION 126N-{(1S,3R)-3-[2-(3-methylphenylthio)ethyl]cyclohexyl}(t-butoxy)carboxamide

3-Methylthiophenol (0.15 mL, 0.0013 mol) was dissolved in DMF (10 mL) atambient temperature under a nitrogen atmosphere and sodium hydride (60%,0.050 g, 0.0013 mol) was added. After stirring for 15 min., the compoundfrom preparation 125 (0.50 g, 0.0013 mol) was added and the mixturestirred overnight at ambient temperature. The mixture was concentratedin vacuo and the residue chromatographed over silica gel usingCH₂Cl₂/THF as eluant which allowed for isolation of 0.42 g (95%) of thedesired product. MS(ES): (M+1)⁺ 350.5 m/z.

PREPARATION 127N-((1S,3R)-3-{2-[3-methylphenyl)sulfonyl]ethyl}cyclohexyl)(t-butoxy)carboxamide

The compound from preparation 126 (0.40 g, 0.00115 mol) was dissolved ina methanol/acetone (10 mL)/(10 mL) mixture and NaHCO₃ (0.40 g, 0.0048mol) and water (5 mL) were added. Oxone® (1.46 g, 0.0024 mol) was thenadded and the mixture stirred at ambient temperature for 3.5 h. Themixture was concentrated in vacuo and the residue taken up in aqueousNaHCO₃ and extracted with CH₂Cl₂. The combined extracts were dried oversodium sulfate and concentrated in vacuo. The resulting residue waschromatographed over silica gel using CH₂Cl₂/THF as eluant which allowedfor isolation of 0.420 g (96%) of the desired sulfone. MS(FD): M⁺ 381.2,382.2 m/z.

PREPARATION 128N-((1S,3R)-3-{2-[(3-methylphenyl)sulfonyl]ethyl}cyclohexyl)[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

The compound from preparation 127 (0.385 g, 0.0010 mol) and TFA (1.0 mL)were dissolved in CH₂Cl₂ (5.0 mL) and the mixture stirred at ambienttemperature for 2 h. The mixture was concentrated in vacuo and theresidue treated with aqueous NaHCO₃ and extracted with CH₂Cl₂. Thecombined extracts were dried over sodium sulfate and concentrated invacuo which allowed for recovery of crude amine. This amine was combinedwith 3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride(0.302 g, 0.0011 mol), triethylamine (0.31 mL, 0.0022 mol) and DMAP(0.010 g, cat.) in CH₂Cl₂ (6.0 mL) and the mixture stirred overnight atambient temperature. The mixture was concentrated in vacuo and theresulting residue chromatographed over silica gel using CH₂Cl₂/THF aseluant which allowed for isolation of 0.463 g (88%) of the desiredamide. MS(ES): (M+1)⁺ 519.2, 521.2 m/z.

PREPARATION 129N-[(1S,3R)-3-(2-phenylthioethyl)cyclohexyl](t-butoxy)carboxamide

Thiophenol (0.32 mL, 0.0031 mol) was combined with sodium hydride (60%,0.15 g, 0.0038 mol) in DMF (15 mL) and a compound from preparation 125(1.25 g, 0.0031 mol) subsequently added in a manner similar topreparation 126. Workup and purification allowed for isolation of 1.0 g(98%) of the desired product. MS(ES): (M+1)⁺ 335.1 m/z.

PREPARATION 130 N-[(1S,3R)-3-(2-phenylthioethyl)cyclohexyl][3-(2-chloro-6-fluorophenyl)-5-methyl]isoxazol-4-yl]carboxamide

The compound from preparation 129 (0.50 g, 0.0015 mol) was combined withTFA (2 mL) in CH₂Cl₂ (10 mL) and treated in a manner similar topreparation 128. The resulting crude amine (0.213 g, 0.00097 mol) wascombined with 3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonylchloride (0.27 g, 0.001097 mol) and triethylamine (0.27 mL, 0.0019 mol)in CH₂Cl₂ (10 mL) again in a manner similar to preparation 128. Workupand purification allowed for isolation of 0.413 g (58%) of the desiredamide.

MS(ES): (M+1)⁺ 473.1, 475.1 m/z.

PREPARATION 131N-((1S,3R)-3-{2-[benzylsulfonyl]ethyl}cyclohexyl)(t-butoxy)carboxamide

Benzyl mercaptan (0.15 mL, 0.0013 mol) was combined with sodium hydride(60%, 0.05 g, 0.0013 mol) in DMF (10 mL) and the compound frompreparation 125 (0.50 g, 0.0013 mol) subsequently added in a mannersimilar to preparation 126. Workup and purification allowed forisolation of 0.27 g (61%) of the desired sulfide. This compound (0.27 g,0.0008 mol) was dissolved in a methanol/acetone (5 mL)/(5 mL) mixtureand NaHCO₃ (0.27 g, 0.0032 mol) and water (5 mL) were added. Oxone®(0.98 g, 0.0016 mol) was then added and the mixture treated in a similarmanner to preparation 127. Workup and purification allowed for isolationof 0.092 g (30%) of desired sulfone intermediate. MS(ES): (M+1)⁺ 382.5m/z.

PREPARATION 132N-((1S,3R)-3-{2-[Benzylsulfonyl]ethyl}cyclohexyl[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

The compound from preparation 131 (0.090 g, 0.00024 mol) was combinedwith TFA (1 mL) in CH₂Cl₂ (3 mL) and treated in a similar manner topreparation 127. The resulting crude amine was combined with3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride(0.067 g, 0.00024 mol), triethylamine (4 drops), and DMAP (0.005 g,cat.) in CH₂Cl₂ (3 mL) again in a manner similar to preparation 126.Workup and purification allowed for isolation of 0.10 g (79%) of thedesired amide.

MS(ES): (M+1)⁺ 519.2, 521.1 m/z.

PREPARATION 133N-{(1S,3R)-3-[2-(3-Fluorophenylthio)ethyl]cyclohexyl}(t-butoxy)carboxamide

3-Fluorothiophenol (0.14 mL, 0.0013 mol) was combined with sodiumhydride (60%, 0.055 g, 0.0014 mol) in DMF (6 mL) and the compound frompreparation 125 (0.50 g, 0.0013 mol) subsequently added in a mannersimilar to preparation 126. Workup and purification allowed forisolation of 0.40 g (89%) of the desired product. MS(ES): (M+1)⁺ 354m/z.

PREPARATION 134N-((1S,3R)-3-{2-[(3-Fluorophenyl)sulfonyl]ethyl}cyclohexyl)(t-butoxy)carboxamide

The compound from preparation 133 (0.38 g, 0.0011 mol) was dissolved ina methanol/acetone (10 mL)/(10 mL) mixture and NaHCO₃ (0.36 g, 0.0043mol) and water (5 mL) were added. Oxone® (1.30 g, 0.0021 mol) was thenadded and the mixture treated in a manner similar to preparation 125.Workup and purification allowed for isolation of 0.40 g (98%) of thedesired sulfone intermediate. MS(ES): (M+1)⁺ 386.3 m/z.

PREPARATION 135N-{(1S,3R)-3-[2-(3-Fluorophenylthioethyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

The compound from preparation 134 (0.030 g, 0.00078 mol) was combinedwith TFA (1.5 mL) in CH₂Cl₂ (6 mL) and treated in a manner similar topreparation 126. The resulting crude amine was combined with3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (0.213g, 0.00078 mol), triethylamine (0.22 mL, 0.0016 mol) and DMAP (0.015 g,cat.) in CH₂Cl₂ (10 mL) again in a manner similar to preparation 126.Workup and purification allowed for isolation of 0.38 g (93%) of thedesired amide.

MS(ES): (M+1)⁺ 523.1, 525.2 m/z.

PREPARATION 136 N-{(1S,3R)-3-[2-(4-Fluorophenylthio)ethyl]cyclohexyl}(t-butoxy)carboxamide

4-Fluorothiophenol (0.16 mL, 0.0015 mol) was combined with sodiumhydride (60%, 0.059 g, 0.0015 mol) in DMF (15 mL) and a compound frompreparation 125 (0.59 g, 0.0015 mol) subsequently added in a mannersimilar to preparation 133. Workup and purification allowed forisolation of 0.52 g (98%) of the desired product. MS(ES): (M+1)⁺ 353.6m/z.

PREPARATION 137N-((1S,3R)-3-{2-[(3-Fluorophenyl)sulfonyl]ethyl}cyclohexyl)(t-butoxy)carboxamide

A compound from preparation 136 (0.50 g, 0.0014 mol) was dissolved in amethanol/acetone (10 mL)/(10 mL) mixture and NaHCO₃ (0.50 g, 0.0060 mol)and water (8 mL) were added. Oxone® (1.83 g, 0.0030 mol) was then addedand the mixture treated in a manner similar to preparation 125. Workupand purification allowed for isolation of 0.50 g (92%) of the desiredsulfone intermediate. MS(ES): (M+Na)⁺ 408.1 m/z.

PREPARATION 138N-((1S,3R)-3-{2-[(4-Fluorophenyl)sulfonyl]ethyl}cyclohexyl)-[3-(6-chloro-2-fluorophenyl)-5-methylisoxazol-4yl]-carboxamide

The compound from preparation 137 (0.45 g, 0.0012 mol) was combined withTFA (2 mL) in CH₂Cl₂ (10 mL) and treated in a manner similar topreparation 126. The resulting crude amine (0.30 g, 0.0011 mol) wascombined with 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonylchloride (0.29 g, 0.0011 mol), triethylamine (0.29 mL, 0.0021 mol) andDMAP (0.010 g, cat.) in CH₂Cl₂ (20 mL) again in a manner similar topreparation 126. Workup and purification allowed for isolation of 0.506g (92%) of the desired amide. MS(ES): (M+1) 523.1, 525.1 m/z.

PREPARATION 139 Diphenylmethyl2-((1R)-3-oxocyclohexyl)propane-1,3-dioate

To a flame dried flask at 0° C. was added lithium aluminum hydride (3.0mL, 3.0 mmol, 1.0M in tetrahydrofuran) followed by(R)-(+)-1,1′-bi-2-napthol (1.71 g, 6.0 mmol) in anhydroustetrahydrofuran (24 mL). After 30 min, the solution was allowed to warmto room temperature. A solution of sodium hydride (108 mg, 2.7 mmol, 60%in mineral oil) and dibenzylmalonate (675 μL, 2.7 mmol) in anhydroustetrahydrofuran (30 mL) was then added to the reaction dropwise overapproximately 2 min. To this mixture were then added 2-cyclohexen-1-one(2.91 mL, 30.0 mmol) and dibenzylmalonate (7.5 mL, 30 mmol), and thereaction was then stirred at room temperature, under a nitrogen atm,overnight. To the reaction was added 1N hydrochloric acid (60 mL, 60mmol, 1N in water), followed by extraction with ethyl acetate (3×200mL). The combined organic layers were then washed with saturated sodiumbicarbonate solution, dried over magnesium sulfate and concentrated.Purification by flash chromatography on silica gel (eluting with 5-7.5%acetone/hexane) gave 10.25 g of the title compound as a opaque solid,90% yield. ¹H NMR: consistent with structure. MS (ion spray) 381 (M⁺+1).

PREPARATION 140 cis-Diphenylmethyl2-(3-hydroxycyclohexyl)propane-1,3-dioate

To a solution of a compound from preparation 139 (6.13 g, 16.1 mmol) intetrahydrofuran (120 mL), methanol (10 mL), and water (10 mL) was addedsodium borohydride (1.22 g, 32.2 mmol). After 10 min., the reaction waspoured into 150 mL of a saturated ammonium chloride solution, andextracted with ethyl acetate. The ethyl acetate layer was washed withadditional saturated ammonium chloride solution, saturated sodiumbicarbonate solution, dried over magnesium sulfate, and concentrated.Purification by flash chromatography on silica gel (eluting with 5-13%acetone/hexane) gave 5.38 g of the title compound as a clear oil, 87%yield. ¹H NMR: consistent with structure. MS (ion spray) 383 (M⁺+ 1).

PREPARATION 141 cis-Phenylmethyl 2-(3-hydroxycyclohexyl)acetate

To a solution of a compound from preparation 140 (5.38 g, 14.07 mmol) inanhydrous methylsulfoxide was added water (0.51 mL, 28.13 mmol) andlithium chloride (1.19 g, 28.13 mmol). The reaction was placed in an oilbath at 175° C. and stirred vigorously for 2.5 h. The reaction was addedto water and extracted with ethyl acetate twice. The organic layer waswashed with water (×2), saturated sodium bicarbonate solution (×2),dried over magnesium sulfate and concentrated. Purification by flashchromatography on silica gel (eluting with 13% acetone/hexane) gave 1.81g of the title compound as a yellow oil, 52% yield. ¹H NMR: consistentwith structure.

PREPARATION 142 cis-Phenylmethyl 2-(3-azidocyclohexyl)acetate

To a solution of a compound from preparation 141 (1.81 g, 7.29 mmol) inanhydrous toluene (70 mL) was added triphenylphosphine (3.82 g, 14.58mmol), Zn(N₃)₃.pyridine₂ (1.68 g, 5.47 mmol), followed by dropwiseaddition of diethyl azodicarboxylate (2.30 mL, 14.58 mmol) overapproximately 15 min., and the reaction was stirred at room temperatureovernight under a nitrogen atmosphere. Filtered through Celite® toremove zinc salts, dilute with ethyl acetate, wash with 0.1N sodiumhydroxide (×3), water, saturated sodium bicarbonate solution, dry overmagnesium sulfate and concentrated. Purification by flash chromatographyon silica gel (eluting with 3.5% ethyl acetate/hexane) gave 652 mg ofthe title compound as an oil, 33% yield. ¹H NMR: consistent withstructure.

PREPARATION 143 cis-Phenylmethyl2-{3-[(t-butoxy)carbonylamino]cyclohexyl}acetate

To a solution of a compound from preparation 142 (652 mg, 2.4 mmol) andt-butoxycarbonyl anhydride (1.10 mL, 4.8 mmol) in ethyl acetate (50 mL)under a nitrogen atmosphere was added Lindlar's catalyst (270 mg, 5% byweight). The mixture was subjected to a hydrogen atmosphere at roomtemperature overnight. The mixture was filtered over Celite® to removethe catalyst and concentrated. Purification by flash chromatography onsilica gel (eluting with 15% ethyl acetate/hexane) gave 820 mg of thetitle compound as a clear oil, 100% yield.

¹H NMR: consistent with structure.

PREPARATION 144 cis-Phenylmethyl2-(3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)acetate

A solution of a compound from preparation 143 in trifluoroacetic acidwas stirred at room temperature for 30 min. The solution wasconcentrated, followed by azeotropic removal of the remaining solventwith acetonitrile (×3). The crude product was dissolved in ethylacetate, washed with 1N sodium hydroxide (×2), dried over magnesiumsulfate and concentrated. To a solution of the resulting oil indichloromethane (20 mL) was added3-(2-chloro-6-fluorophenyl)-5-methylisoxazole4-carbonyl chloride (748mg, 2.72 mmol), triethylamine (1.03 mL, 7.43 mmol), and dimethylaminopyridine (30 mg, 0.25 mmol), followed by triethylamine (1.03 mL, 7.43mmol) dropwise via syringe. The reaction was stirred overnight undernitrogen at room temperature. The solution was washed with 0.1N HCl(×3), water, saturated sodium bicarbonate solution, dried over magnesiumsulfate and concentrated. Purification by flash chromatography on silicagel (eluting with 0-30% ethyl acetate/hexane) gave 1.13 g of the titlecompound as a clear oil, 94% yield. ¹H NMR: consistent with structure.

PREPARATION 1452-[3-(9-Chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]aceticAcid

To a solution of a compound from Example 494 (291 mg, 0.63 mmol) indioxane (5 mL) was added 5N NaOH (5 mL) and the solution heated toreflux for 1 h. Upon cooling the reaction was quenched with 1Nhydrochloric acid, and extracted with 20% isopropanol/chloroform (×3),dried over magnesium sulfate and concentrated. The resulting brown oilwas treated with ethyl ether, sonicated, and a brown solid filtered out,to give 164 mg of the title compound, 70% yield. ¹H NMR: consistent withstructure.

PREPARATION 146trans-5-[3-(Aminomethyl)cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-oneHydrochloride

To trans-racemic[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]carbamicacid t-butyl ester (1.22 g, 2.74 mmol) was added acetic acid saturatedwith HCl_((g)) (30 mL, ˜3N in HCl)and the solution stirred vigorously atroom temperature for 10 min. The reaction was concentrated, followed byaddition of acetonitrile and concentrated to assist in the removal ofacetic acid. The resulting white solid was treated with ethyl ether,sonicated, and filtered to yield 985 mg of the title compound as a whitesolid, 94% yield. ¹H NMR: consistent with structure. MS (ion spray) 346(M⁺+1).

PREPARATION 147 2-Fluoro-3-iodobenzaldehyde

To a solution of diisopropylamine (10.42 mL, 74.36) in THF (135 mL)under N₂ in an ice bath at 0-5° C. was added dropwise over 10 min n-BuLi(42.25 mL, 67.6 mmol) and stirred at this temperature for 10 min. Cooledthe reaction mixture to −78° C. in a dry ice/acetone bath and dropwiseadded 1-fluoro-2-iodobenzene (7.88 mL, 67.6 mmol) over 5 min. Stirred atthis temperature for 1 h, dropwise added DMF (6.26 mL, 74.36 mL) over 5min, and stirred for 10 min. Added Acetic Acid (13.5 mL) followed by H₂Oand extracted with Et₂O (2×). The combined organic solution was washed(0.1 N HCl then brine), dried (MgSO₄), filtered and concentrated. Thecrude benzaldehyde (16.9 g) was taken onto the next step withoutpurification. ¹H NMR was consistent with structure.

PREPARATION 148 2-Fluoro-3-iodobenzaldoxime

To a mixture of a compound from preparation 147 (16.9 g, 67.6 mmol) inH₂O (35 mL), EtOH (35 mL), and ice (25 g) was added hydroxylaminehydrochloride (4.8 g, 74.4 mmol). Then, 169 mmol of 50% NaOH (6.76 g in6.76 mL H₂O) was added with stirring. Enough ice to keep the temperatureat 25-30° C. was added. Stirred for 2.5 h, acidified with conc. HCl topH 4 (ice was added to keep the temperature at 25-30° C.), and extractedwith Et₂O (2×). The combined organic solution was washed (brine), dried(MgSO₄), filtered, and concentrated. The residue was chromatographed onsilica gel (EtOAc/dichloromethane gradient) to give the title compound(8.02 g, 45% over 2 steps).

Mass Spectrum (FIA) (m/z) 264.0 [M-1].

PREPARATION 149 2-Fluoro-3-iodobenzohydroximinoyl Chloride

To a stirred solution of a compound from preparation 148 (8.02 g, 30.2mmol) in DMF (45 mL) at 25-30° C. was added about ⅕ of 30.2 mmol (4.03g) of NCS. The initial NCS addition results in a slight temperaturedecrease. If the reaction does not self-initiate within 10 min., asindicated by a slight temperature rise, 5 pipettes of gas from theheadspace of a conc. HCl reagent bottle was bubbled into the DMFsolution. Carefully added rest of NCS and temperature rose to 45-55° C.Once reaction cooled to r.t. (about 1 h), added ice H₂O and extractedwith Et₂O (2×). The combined organic solution was washed with (brine),dried (MgSO₄), filtered, and concentrated. The title compound (9.04 g)was taken on to the next step without purification. ¹H NMR wasconsistent with structure.

PREPARATION 150 Ethyl3-(6-fluoro-2-iodophenyl)-5-methylisoxazole-4-carboxylate

To a solution of a compound from preparation 149 (30.2 mmol) andethyl-2-butynoate (4.23 mL, 36.24 mmol) in Et₂O (120 mL) under N₂stirring at 0-5° C. was added dropwise a solution of Et₃N (5.46 mL,39.26 mmol) in Et₂O (17 mL) over 1 h. Allowed to warm to roomtemperature and stirred overnight. Added Et₂O and washed (H₂O thenbrine), dried (MgSO₄), filtered, and concentrated. The crude residue waschromatographed on silica gel (dichloromethane) to give the titlecompound (6.92 g, 61%). Mass Spectrum (FIA) (m/z) 376.15 [M+1].

PREPARATION 153 N-t-Butyl-N′-(2-chloro-6-fluorobenzylidene)hydrazineHydrochloride

A mixture of t-butyl hydrazine hydrochloride (1.24 g, 10 mmol) and2-chloro-6-fluorobenzaldehyde (1.1 mL, 10 mmol) dissolved in acetic acid(5 mL) was stirred at 50° C. for half hour. Hexanes (10 mL) was added,filtered and washed the white solid with hexanes (20 mL). Yield: 61%.ESMS: 229 (M+1).

PREPARATION 1563-Methyl-5-(2-chloro-6-fluorophenyl)-4-isoxazolecarboxylic Acid EthylEster

To a solution of ethyl 3-aminomethyl crotonate (4.79 g, 33.5 mmol) intoluene (10 mL), was added triethylamine (3.73 g, 37 mmol). The solutionwas chilled using an ice bath, and then 2-chloro-6-fluorobenzoylchloride (6.47 g, 33.5 mmol) was added dropwise over a 20 min period.The reaction was allowed to warm slowly to r.t. and stirred for 24 hr.The resulting suspension was then filtered, and the filtrate dilutedwith ethyl acetate (100 mL) and transferred to a separatory funnel. Theorganic layer was sequentially washed with water, brine, dried (sodiumsulfate), and the volatiles removed under reduced pressure to providethe title compound (9.46 g) as a golden solid, and primarily onegeometrical isomer. MS (ES) m/z 299.9 (M+H)⁺.

The crude adduct was then redissolved in glacial HOAc (50 mL) to whichwas added NH₂OH.HCl (1.8 g, 1.1 eq). The solution was then heated toreflux for 40-45 min to effect isoxazole formation. The reaction mixturewas concentrated to an oil, diluted with ether, and transferred to asep. funnel. The organic phase was washed with saturated bicarbonate,brine, then dried. Filtration and concentration afforded crude isoxazoleethyl ester (7.5 g), which was used without further purification. MS (+ES) m/z 283.9 (M+H)⁺.

PREPARATION 1575-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylic Acid

Hydrolysis of the ethyl ester was accomplished by dissolving the crudeester (7.5 g, approx. 0.027 mol) in THF (250 mL), and adding aq. LiOH(1.344 g in 100 mL, 2 eq). After stirring overnight at r.t., thesolution was concentrated to ⅔^(rd) volume, diluted with EtOAc (200 mL)and 50 mL water, transferred to a separatory funnel, and the aqueousphase collected. The organic phase was washed twice, and the combinedaqueous phase was then acidified with 5N HCl. Back extraction with threewashings of EtOAc was then followed with a brine wash of the combinedorganics. After drying over Na₂SO₄, filtration and concentration, cleanisoxazole acid was obtained (2.94 g). NMR (CDCl₃) δ7.13, 7.32 7.46 (3 m,3H), 2.58 (s, CH₃). MS (−ES) m/z 253.8, 255.8 (M−H)⁻.

PREPARATION 1582-(3-{[5-(2-chloro-6-fluorophenyl)-3-methylisoxazol-4-yl]carbonylamino}cyclohexyl)-N-(3,4,5-trimethoxyphenyl)acetamide

To a compound from preparation 157 (60 mg, 0.234 mmol) in benzene (4 mL)containing catalytic amount of pyridine (20 μl) was added oxalylchloride (23 mL). After heating to reflux for 1 hr, an aliquot wasconcentrated under vacuum and analyzed by 1H—NMR (CDCl₃) for completionof acid chloride formation; 1H—NMR (CDCl₃) 7.53 (d of t, 1H), 7.37 (d,1H), 7.17 (t,1 H). (racemic)

Solvent was removed under vacuum. To a solution ofd,1-cis-1-amino,3-(N-3,4,5-trimethoxyphenyl)cyclohexyl-acetamide (60 mg,0.185 mmol) in dry MeCl₂ (4 mL) containing catalytic DMAP (10%) andpyridine (20 μl, 0.24 mmol) was added the crude acid chloride in 0.5 mLMeCl₂ at r.t. Reaction was allowed to proceed for 4 hr at which timeamide formation was complete by TLC. The reaction was diluted with MeCl₂and transferred to a sep funnel, washed with dil.HCl (pH 1), and theaqueous fraction was separated and reextracted two more times in thesame manner. The combined organics were then washed sequentially withsat'd bicarbonate, brine, dried over Na₂SO₄, filtered and concentratedunder vacuum to afford crude product (69 mg). Purification wasaccomplished via prep TLC (Chromatotron®, 1 mm SI plate) using 70%-90%EtOAc in hexane to obtain 24 mg (24% from amine). MS (+ES) m/z 559.9(M+H), 576.9 (M+NH₃).

PREPARATION 159(3-{[5-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carbonyl]amino}cyclohexyl)aceticacid ethyl ester (cis)

A compound from preparation 157 (254 mg, 1 mmol) was dissolved in DMF(15 mL). EDC.HCl (211 mg, 1.1 eq) was then added, followed by DMAP (10mg), and then cis-1,3-1(S)aminocyclohexyl-3(R)-acetic acid, methyl ester(60% ee, 188 mg, 1.1 eq) at r.t. After 18 hr, starting material was notyet fully consumed (TLC, NMR of aliquot), so the mixture was heated to80° for 2 hr. The reaction was then cooled to r.t., and diluted withEtOAc and 0.1 N HCl. The aqueous phase was reextracted twice, and thecombined organics washed with sat'd bicarbonate, brine, dried overNa₂SO₄. Filtration and concentration afforded crude product (207 mg).Purification using a Bond-Elut SI column (10 g, 4:3 hex/EtOAc) provided34 mg (8%) of the title compound. MS (+ES) 411.0 (M+H)+.

PREPARATION 160(3-{[5-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carbonyl]amino}cyclohexylmethyl)carbamicacid t-butyl ester

Using the acid chloride method described for preparation 158, 3 mmol(0.689 g) of a cis/trans mixture of 1-amino, 3-Boc-aminomethylenecyclohexane was dissolved in CH₂Cl₂ (10 mL), followed by addition ofEt₃N (0.415 mL, 6 mmol), DMAP (cat, 20 mg), at rt. The above isoxazoleacid chloride of preparation 157 (3 mmol in 10 mL CH₂Cl₂) was then addeddropwise over 10 min. Reaction was allowed to proceed overnight. Thereaction mixture was then transferred to a sep funnel, diluted withadditional CH₂Cl₂, and washed sequentially with 5% citric acid (aq, pH3-4), sat'd bicarbonate, brine, then dried. Filtration and concentrationyielded crude product (brown oil). Purification by filtration through apad of Silica Gel 60 in a 60 mL sintered glass funnel using 2:1hexane/EtOAc afforded clean cis/trans product (0.830 g, 59% overall).NMR (CDCl₃) δ 7.2-7.6 (3 m,3H), 5.55 and 5.2 (trans/cis amide NH's), 4.5and 4.2 (cis/trans Boc NH's), 3.8 and 2.95 (trans/cis aminomethine(CH)), 2.58 and 2.55 (trans/cis CH3), 0.6-2.9 (m's), 1.4 (2 s, cis/transt-butyl). MS (+ES); 465.9 (N+H)⁺; (−ES); 463.9 (M−H)⁻, 499.9 (M+Cl−H)⁻,524 (M+Oac−H)⁻.

PREPARATION 161 (cis-3(S)-Aminocyclohexylmethyl)carbamic Acid BenzylEster

S-amino enantiomer of N-({3-[(t-butoxy)carbonyl-amino]cyclohexyl}methyl)(phenylmethoxy)carboxamide (1.0 g, 2.76 mmol) was treated with TFA (5mL) under N₂. After 20 min of stirring at r.t. the reaction wascomplete. The crude was then concentrated to an oil which was purifiedon a Varian Bond-Elut SCX column (10 g). The column was elutedconsecutively with CHCl₃, MeOH, and ammonia (2.0M in MeOH). The pureproduct was recovered from the ammonia fractions. The solvent wasremoved in vacuo to afford 0.632 g (87%) as a colorless oil. MS (ES+)m/z 263.0 (M+H)⁺.

PREPARATION 162(3-{[5-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carbonyl]amino}cyclohexylmethyl)carbamicAcid Benzyl Ester

A solution from preparation 157 (1.0 g, 3.9 mmol) in toluene (30 mL) wastreated with a catalytic amount of pyridine (0.1 mL) and cooled to 0° C.The solution was then treated with oxalyl chloride (0.545 g, 4.3 mmol)and stirred at r.t. for 2 hr. 1H NMR showed the completion of the acidchloride formation; 7.52 (d, 1H), 7.37 (d, 1H), 7.15 (t, 1H) The solventwas removed in vacuo. A solution from preparation 161 (0.550 g, 2.09mmol) and triethylamine (0.422 g, 4.18 mmol) in dry DMF (25 mL) wasstirred at r.t. This solution was then treated with the acid chloridefrom preparation 158(0.859 g, 3.135 mmol) which was added dropwise overtwo min. The reaction was then catalyzed with DMAP (0.025 g, 0.21 mmol)and allowed to stir o.n. The reaction was diluted in EtOAc (250 mL),transferred to a sep funnel, and washed with a 5% citric acid solution(5×50 mL), sat. sodium bicarbonate solution (2×50 mL), brine (2×50 mL)and was dried over sodium sulfate. The EtOAc solution was filtered andthe solvent removed in vacuo to yield an orange solid. The solid waspurified using silica gel column chromatography. The column was preparedwith CHCl₃ and the product was eluted with 10% EtOAc in CHCl₃. Thesolvent was removed in vacuo to afford 0.584 g (56%) of the titlecompound as a white solid. MS (ES+) m/z 500.1 (M+H)⁺.

PREPARATION 163 cis-Octahydroquinolin-2-one

To a solution of 2-nitrocinnamic acid in 120 mL of acetic acid in a Parrshaker, was added PtO₂ (10 g). Hydrogen (3 atm) was then introduced, andthe contents of the shaker were heated to 60° C. for 24 h. After themixture was cooled to r.t. and filtered through Celite®, the solvent wasremoved in vacuo, and the residue was dissolved in EtOAc, andtransferred to a sep. funnel. Treatment with sat'd HCO³⁻, brine, andthen drying over Na₂SO₄, filtration and concentration affordedpredominantly cis lactam (<7% trans by NMR) in 55% yield (6 g). MS (+ES)m/z 254 (M+1)⁺.

PREPARATION 164 trans-Octahydroquinolin-2-one

To a solution of 3,4,5,6,7,8-hexahydro-1H-quinoline-2-one (0.1 g, 0.66mmol) in dioxane (10 mL) containing a catalytic quantity (40 μL) wasadded NaCNBH₃ (0.67 g). The reduction was left to stir for 20 hrs atr.t., and then diluted with EtOAc. The organic phase was treated withdilute HCl (3×), and the combined organics were washed with saturatedHCO³⁻, brine, dried over Na₂SO₄, filtered and concentrated to afford themainly traits product (98 mg, 95%, 15-20% cis isomer). MS (+ES) m/z 254(M+1)⁺.

PREPARATION 165cis-3-(2-{[5-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carbonyl]amino}cyclohexyl)propionicAcid Methyl Ester

The acid chloride (0.4 mmol) of preparation 157 was prepared asdescribed previously, and added to a MeCl₂ solution (10 mL) of methyl3-((1S,2S)-2-aminocyclohexyl)propanoate (222 mg, 1.2 eq) followed byEt₃N (133 μl, 0.96 mmol) and DMAP (10%) at r.t. Acylation was allowed toproceed for 18 hr. Crude product was obtained by dilution of thereaction mixture with MeCl₂ and 0.1 N HCl, transferring to a sep funnel.The organic phase was then washed with sat'd bicarbonate, brine, thendried over Na₂SO₄. Filtration and concentration provided crude product,which was then purified using a Bond-Elut Si column (1 g, 1:1 hex/EtOAc)to generate pure methyl ester, (86 mg, 51%). MS (+ES) m/z 422.9/424.9(M+H).

PREPARATION 166cis-3-(2-{[5-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carbonyl]amino}cyclohexyl)propionicAcid

To a solution of a compound from preparation 165 (86 mg, 0.2 mmol) inTHF (5 mL) was added 2 mL 0.5M aq. LiOH (5 eq), dropwise at r.t.Hydrolysis was complete at 2.5 hr. After dilution with water and EtOAc,the contents were transferred to a sep funnel, where addition of enough1N HCl was added to maintain pH 2. The aqueous phase was back extracted3 times with additional solvent, and the combined organics were thenwashed with brine, dried over Na₂SO₄. Filtration and concentrationafforded clean acid, 80 mg (97%), which was used without furtherpurification. MS (+ES) m/z 408.9/410.9 (M+H).

PREPARATION 1675-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylicacid-{2-[2-(3,4,5-trimethoxyphenylcarbamoyl)ethyl]cyclohexyl}amide

To a compound from preparation 166 (40 mg, 0.1 mmol) in DMF (2 mL) wasadded catalytic amount of DMAP (10%, 1 mg), followed by EDC.HCl (20.6mg, 0.11 mmol) and 3,4,5-trimethoxyaniline (20.1 mg, 0.11 mmol) at r.t.After 18 hr, the reaction was transferred to a sep funnel and dilutedwith EtOAc and 1N NaOH (aq. pH 9-10). The aqueous phase was extracted 3times, and combined EtOAc fractions were then washed sequentially with 1N HCl, sat'd bicarbonate, brine, and then dried over Na₂SO₄. Afterfiltration and concentration, crude amide was obtained (33 mg). Startingmaterial (7 mg) was also recovered from the aqueous fraction uponacidification and standard workup. The crude product was thenchromatographically purified (Bond-Elut Silica column, 1 g, 2:1EtOAc/hexanes) to afford clean amide (48 mg, 50%). MS (ES+) 573.9, 575.9(M+H)⁺.

PREPARATION 168trans-3-(2-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}cyclohexyl)propionicAcid

A solution of methyl3-(2-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)propanoate(0.127 g, 0.3 mmol) in THF (5 mL) was treated with a 0.5 M sol'n of LiOHin water (3 mL). The sol'n was stirred at r.t. for 5 hr. The reactionwas diluted with water (3 mL) and washed with EtOAc (2×5 mL). The pH ofthe aqueous was adjusted to ˜3 with 0.1 M HCl and extracted with EtOAc(4×5 mL). The organic extractions were then washed with brine (2×5 mL),dried over sodium sulfate and the solvent removed to afford 0.095 g(80%) as a white solid. MS (ES+) m/z 409.0 (M+H)⁺, (ES−) m/z 407.0(M−H)⁻.

PREPARATION 169

traits-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylicacid{2-[2-(3,4,5-trimethoxyphenylcarbamoyl)ethyl]cyclohexyl}amide

A sol'n of a compound from preparation 168 (0.095 g, 0.23 mmol) and EDC(0.115 g, 0.6 mmol) in DMF (25 mL) was treated with3,4,5-trimethoxyaniline (0.11 g, 0.6 mmol). A catalytic amount of DMAP(4 mg, 0.03 mmol) was also added. The reaction mixture was stirred atr.t. overnight. The reaction was diluted in EtOAc (100 mL) and washedwith 5% citric acid sol (3×50 mL), water (2×50 mL), and dried oversodium sulfate. The solvent was removed in vacuo to afford a crude brownoil which was purified by a Varian Bond Elut SI column (10 g) with aneluting solvent of 1:1 Hexanes: EtOAc. The solvent was removed in vacuoto afford 0.072 g (54%) as an off white solid.

MS (ES+) m/z 574.0 (M+H)⁺, (ES−) m/z 572.1 (M−H)⁻, 632.1 (M+CH₃COO⁻)⁻.

PREPARATION 170 {(3S,1R)-3-[(t-butoxy)carbonylamino]cyclopentyl}-N-benzylcarboxamide

A mixture of N—BOC-1R, 3S-1 amino cyclopentane-3-carboxylic acid (229mg, 1 mmol), EDC (286 mg, 1.5 mmol), benzyl amine (160 mg, 1.5 mmol) andDMAP (5 mg, catalytic) dissolved in DMF (20 mL) was stirred overnight atrt. The reaction mixture was diluted with ethyl acetate (200 mL) andwashed with 0.2M HCl (2×50 mL), water (2×50 mL), brine (2×50 mL), driedover Na₂SO₄, filtered, and evaporated to yield a white solid (160 mg,50%). ESMS: 319 (M+1)⁺.

PREPARATION 171(1R,3S)-1-Amino-N′-phenylmethylcyclopentane-3-carboxamide

A compound from preparation 170 (100 mg, 0.31 mmol) was dissolved in TFAreagent (9.25 mL TFA, 0.25 mL anisole, 0.25 mL TIS, 0.25 mL water) andstirred at r.t for 30 m. TFA reagent was evaporated and the residue wasdissolved in chloroform (10 mL) and filtered through SCX column andeluted with ammonia (10 mL, 2 M solution in methanol) and evaporated toyield title compound (68 mg, quantitative). ESMS: 219 (M+1)⁺, 277(M+Ac)⁺.

PREPARATION 172 {(3S,1R)-3-[N-benzylcarbamoyl]cyclopentyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

A compound from preparation 171 was dissolved in DMF (25 mL) and2-chloro-6-fluorophenyl isoxazoyl chloride, triethylamine and DMAP wereadded and stirred overnight at r.t. The reaction mixture was dilutedwith ethyl acetate (100 mL) and washed with HCl (1M, 2×50 mL), water(2×50 mL), brine (2×50 mL), dried over sodium sulfate, filtered, andevaporated to yield title compound (248 mg, 80%, crude). ESMS: 456 (M)⁺.

PREPARATION 173 (3S,1R)(3-Hydroxymethylcyclopentyl)carbamic Acid t-butylEster

(1R,3S)-3-t-Butoxycarbonylaminocyclopentanecarboxylic acid (229 mg, 1mmol) was dissolved in THF (10 mL) and borane-THF (1.5 mL, 1M solution)was added drop-wise at 0° C. and stirred overnight at r.t. The reactionmixture was poured into ice-cold water (10 mL) and extracted with ethylacetate (2×50 mL). The ethyl acetate extract was washed with brine,dried over sodium sulfate, filtered and evaporated to yield a semi solid(160 mg, 74%). ESMS (+): 216 (M+1)⁺, 250 (M+Cl)⁺.

PREPARATION 174 (3R,1S)-Toluene-4-sulfonic acid3-t-butoxycarbonylaminocyclopentylmethyl Ester

A compound from preparation 173 (150 mg, 0.69 mmol) was dissolved inmethylene chloride (20 mL) and p-toluenesulfonyl chloride (131 mg, 0.69mmol), triethylamine (268 μL, 1.86 mmol) and DMAP (10 mg) were added andstirred overnight. The methylene chloride solution was washed with 1MHCl (2×10 mL), water (2×10 mL), brine (2×10 mL), dried over sodiumsulfate, filtered and evaporated to yield the title compound (223 mg,86%). ESMS: 370 (M+1)⁺, M+Ac)⁺.

PREPARATION 175 (1R,3S)(3-Azidomethyl-cyclopentyl)-carbamic acid t-butylEster

To a solution of a compound of preparation 174 (96 mg, 0.26 mmol)dissolved in DMF (10 mL) sodium azide was added and stirred at 80° C.overnight. The reaction mixture was diluted with ethyl acetate (50 mL)and washed with water (2×25 mL), brine (2×25 mL), dried over sodiumsulfate, filtered and evaporated to yield the title compound (55 mg, 88%crude). HNMR (CDCl₃): 1.00-1.12 (m, 1H), 1.2-1.50 (m, 2H), 1.40 (s, 9H),1.52-1.70 (m, 1H), 1.71 (1.82 (m, 1H), 1.89-2.00 (m, 1H), 2.10-2.30 (m,2H), 3.26-3.28 (d, 2H), 4.80 (br S, 1H).

PREPARATION 176 (1R,3S)(3-Aminomethylcyclopentyl)carbamic Acid t-butylEster

To a solution of a compound from preparation 175 (55 mg, 0.23 mmol)dissolved in methanol (10 mL) palladium/C (10 mg, 10%) was added andstirred under hydrogen (balloon) at for 2 h at rt. The solution wasfiltered off through Celite® and evaporated to yield a white solid (44mg, 89%). ESMS: 215 (M+1)⁺.

PREPARATION 177 (1R,3S)-[3-(Benzoylaminomethyl)cyclopentyl]carbamic Acidt-butyl Ester

To a solution of a compound from preparation 176 (44 mg, 0.2 mmol)dissolved in DMF (10 mL), benzoyl chloride (35 mg, 0.25 mmol),triethylamine (0.5 mL) and DMAP (5 mg) was added and stirred overnightat rt. The reaction mixture was diluted with ethyl acetate (50 mL),washed with 1M HCl (2×20 mL), water (2×20 mL), brine (2×20 mL), driedover sodium sulfate, filtered and evaporated to get title compound (70mg, crude quantitative). ESMS: 319 (M+1)⁺, 317 (M−1)⁻, 353 (M+Cl)⁻, 317(M+Ac)⁻.

PREPARATION 178 (1R,3S)—N-(3-Aminocyclopentylmethyl)benzamide

A compound from preparation 177 (70 mg, 0.22 mmol) was dissolved in TFA(5 mL) and stirred for ½ h at rt. TFA was evaporated under vacuum andthe residue was dissolved in chloroform (5 mL) passed through SCX column(Varian Bond Elut, 6 cc) and eluted with 2M ammonia (methanol) to obtaintitle compound (34 mg, 72%). ESMS: 219 (M+1)⁺, 277 (M+Ac)⁻.

PREPARATION 179(1R,3S)-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylicAcid[3-(benzoylaminomethyl)cyclopentyl]amide

To a solution of a compound from preparation 178 (34 mg, 0.15 mmol) inDMF (5 mL), 2-chloro-6-fluorophenyl isoxazoyl chloride (85 mg, 0.3mmol), triethylamine (1 mL), DMAP (5 mg) were added and stirredovernight. The reaction mixture was diluted with ethyl acetate (50 mL),washed with 1M HCl (2×20 mL), water (2×25 mL), brine (2×20 mL), driedover sodium sulfate, filtered, evaporated and chromatographed (silicagel, 50% ethyl acetate in hexanes) to yield title compound (36 mg, 52%).ESMS: 456 (M)+, 514 (M+Ac)⁻.

PREPARATION 180 (1S,4R)(4-Hydroxymethyl-cyclopent-2-enyl)-carbamic Acidt-butyl Ester

To a solution of 4-t-butoxycarbonylaminocyclopent-2-enecarboxylic acid(1 g, 4.4 mmol) dissolved in THF (100 ml) and added with borane-THF (4.5ml, 4.5 mmol) at 0° C. and stirred overnight at r.t. The reactionmixture was poured into ice-cold water (100 ml) and extracted with ethylacetate. The ethyl acetate extract was washed with brine, dried oversodium sulfate and evaporated to obtain the title compound (655 mg,69%). ESMS: 214 (M+1)⁺, 236 (M+23)⁺, 248 (M+35)⁻, 272 (M+59)⁻.

PREPARATION 181

(1S,4R)-Toluene-4-sulfonic Acid4-t-butoxycarbonylamino-cyclopent-2-enylmethyl Ester

A solution of a compound from preparation 180 (655 mg, 3 mmol), p-tosylchloride (760 mg, 4 mmol), triethyl amine (0.4 ml) and DMAP (100 mg)dissolved in dichloromethane (50 ml) was stirred at rt, overnight. Thereaction mixture was washed with dilute hydrochloric acid (2×), water(2×), brine (2×), dried over sodium sulfate and evaporated to obtain thetitle compound (1.0 g, 90%). ESMS: 368 (M+1)⁺, 426 (M+59)⁻.

PREPARATION 182 (1S,4R)(4-Azidomethylcyclopent-2-enyl)carbamic Acidt-butyl Ester

To a solution of a compound from preparation 181 (2 g, 2.7 mmol) in DMF(50 mL), sodium azide (200 mg, 3 mmol) was added and stirred at 80° C.overnight. The reaction mixture was diluted with ethyl acetate (100 mL)and washed with water (2×50 mL), brine (2×50 mL), dried over sodiumsulfate and evaporated to yield the title compound (quantitative). IR(chloroform): 2096.6 cm⁻ (azide). ¹HNMR (CDCl₃): δ1.27-1.30 (m, 2H),1.43 (s, 9H), 2.51-2.56 (m, 2H), 3.27-3.35 (m, 2H), 5.76 (s, 2H).

PREPARATION 183 (1S,3R)-(3-Aminomethylcyclopentyl)carbamic Acid t-butylEster

To a solution of a compound from preparation 182 (300 mg, 1.25 mmol) inmethanol (10 mL), Pd/C (10%, 50 mg) was added and the reaction mixturewas hydrogenated (1 atm) overnight at rt. The reaction mixture wasfiltered through celite and evaporated to yield the title compound (222mg, 89%). ESMS: 215 (M+1)⁺.

PREPARATION 184

(1S,3R)[3-(Benzoylaminomethyl)cyclopentyl]carbamic Acid t-butyl Ester

A mixture of a compound from preparation 183 (222 mg, 1.03 mmol),benzoyl chloride (210 mg, 1.5 mmol), triethylamine (1 mL), and DMAP (10mg, catalytic) in DMF (50 mL) was stirred overnight. The reactionmixture was diluted with ethyl acetate (100 mL) and washed with dilutehydrochloric acid (1M, 2×50 mL), water (2×50 mL), brine (2×50 mL), driedover sodium sulfate, filtered and evaporated to yield the title compound(395 mg). ESMS: 319 (M+1)⁺, 377 (M+59)⁻.

PREPARATION 185 (1S,3R)—N-(3-Aminocyclopentylmethyl)benzamide

A compound from preparation 184 (crude 390 mg) was dissolved intrifluoroacetic acid (10 mL) and stirred for half an hour at rt. Thereaction mixture was evaporated and chromatographed (Varian Bond Elut 60cc, SCX column, 2M ammonia solution in methanol) to obtain the titlecompound (233 mg, 87%). ESMS: 219 (M+1)⁺.

PREPARATION 186(1S,3R)-3-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylicAcid[3-(benzoylaminomethyl)cyclopentyl]amide

A mixture of a compound from preparation 185 (230 mg, 1.05 mmol),3-(2-chloro, 6-fluorophenyl)-5-methyl-4-isoxazoyl chloride (328 mg, 1.2mmol), triethyl amine (1 mL), dimethyl amino pyridine (DMAP, 50 mg)dissolved in DMF (20 mL) was stirred overnight at rt. The reactionmixture was diluted with ethyl acetate (100 mL) and washed with diluteHCl (1M, 2×50 mL), water (2×50 mL), brine (2×50 mL), dried over sodiumsulfate, filtered, evaporated and then chromatographed (Varian BondElut, Si, 60 cc, 50% EtOAc in Hexane) to obtain the title compound (100mg, 20%). ESMS: 456 (M)⁺, 515 (M+59)⁻.

PREPARATION 187(1S,3R){3-[(4-Fluorobenzoylamino)methyl]cyclopentyl}carbamic Acidt-butyl Ester

To a solution of a compound from preparation 183 (68 mg, 0.31 mmol) and4-fluorobenzoylchloride (60 mg, 0.38 mmol) dissolved in DMF (2 mL),triethyl amine (0.5 mL) and DMAP (10 mg) were added and stirred for fourhours at rt. The reaction mixture was diluted with ethyl acetate (20 mL)and washed with dilute hydrochloric acid (2×20 mL, 0.1 M), water (2×20mL), brine (2×20 mL), dried over sodium sulfate, filtered and evaporatedto obtain 492323 (127 mg). ESMS: 337 (M+1)⁺, 395 (M+59)⁻.

PREPARATION 188 (1S,3R)—N-(3-Aminocyclopentylmethyl)-4-fluorobenzamide

A compound from preparation 187 (127 mg) was dissolved intrifluoroacetic acid (2 mL) and stirred for half an hour at rt. Thereaction mixture was evaporated under vacuum and the residue wasdissolved in methylene chloride, filtered through SCX column (Bond Elut,60 cc) and eluted with ammonia (2M in methanol) to obtain the titlecompound (81 mg, 91%). ESMS: 237 (M+1)⁺, 295 (M+59)⁻.

PREPARATION 189(1R,3S)-3-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylicAcid{3-[(4-fluorobenzoylamino)methyl]cyclopentyl}amide

A solution of a compound from preparation 188 (81 mg, 0.34 mmol), chlorofluoro phenyl isoxazoyl chloride (113 mg, 0.41 mmol), triethyl amine(0.5 mL) and DMAP (10 mg) in DMF (5 mL) was stirred overnight at rt. Thereaction mixture was diluted with ethyl acetate (20 mL) and washed withdilute hydrochloric acid (2×20 mL, 0.1 M), water (2×20 mL), brine (2×20mL), dried over sodium sulfate, filtered and evaporated to obtain thetitle compound (80 mg, crude, 50%, used directly in the next step).ESMS: 474 (M)⁺, 475 (M+1)⁺, 533 (M+59)⁻.

PREPARATION 190(1S,3R)(3-{[(Biphenyl-4-carbonyl)amino]methyl}-cyclopentyl)carbamic Acidt-butyl Ester

A solution of a compound from preparation 183 (68 mg, 0.31 mmol),4-phenyl benzoyl chloride (82 mg, 0.38 mmol), triethyl amine (0.5 mL),and DMAP (10 mg) dissolved in DMF (2 mL) was stirred for four hours atrt. The reaction mixture was diluted with ethyl acetate (20 mL) andwashed with dilute hydrochloric acid (2×20 mL, 0.1 M), water (2×20 mL),brine (2×20 mL), dried over sodium sulfate, filtered and evaporated toobtain the title compound (170 mg, crude, used without purification).

ESMS:395 (M+1)⁺, 453 (M+59)⁻.

PREPARATION 191 (1S,3R)-Biphenyl-4-carboxylic acid(3-amino-cyclopentylmethyl)amide

A compound from preparation 190 (170 mg, crude) was dissolved intrifluoro acetic acid (2 mL) and stirred for half an hour. The reactionmixture was evaporated under vacuum and the residue was dissolved inmethylene chloride and filtered through sox column (Bond Elut, 60 cc)and eluted with methanol-ammonia solution (2M) to obtain the titlecompound (63 mg). ESMS: 295 (M+1)⁺, 353 (M+59)⁻

PREPARATION 192(1S,3R)-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic Acid(3-{[(biphenyl-4carbonyl)amino]methyl}-cyclopentyl)amide

A solution a compound from preparation 191 (63 mg, 1.21 mmol),2-chloro-6-fluoro phenyl isoxazoyl chloride (88 mg, 0.32 mmol), triethylamine (0.5 mL), and DMAP (10 mg) dissolved in DMF (5 mL) was stirred forfour hours at rt. The reaction mixture was diluted with ethyl acetate(20 mL) and washed with dilute hydrochloric acid (2×20 mL, 0.1 M), water(2×20 mL), brine (2×20 mL), dried over sodium sulfate, filtered andevaporated to obtain the title compound (61 mg, 54%, used withoutpurification).

ESMS: 532 (M)⁺, 533 (M+1)⁺, 591 (M+59)⁻.

PREPARATION 193(1S,3R)(3-{[(Pyridine-3-carbonyl)amino]methyl}cyclopentyl)-carbamic Acidt-butyl Ester

A solution of a compound from preparation 183 (68 mg, 0.31 mmol),nicotinoyl chloride (54 mg, 0.38 mmol), triethyl amine (0.5 mL), andDMAP (10 mg) dissolved in DMF (2 mL) was stirred for four hours at rt.The reaction mixture was diluted with ethyl acetate (20 mL) and washedwith water (2×20 mL), brine (2×20 mL), dried over sodium sulfate,filtered and evaporated to obtain the title compound (58 mg, 59%, usedwithout purification). ESMS: 318 (M−1)⁻, 378 (M+59)⁺.

PREPARATION 194 (1S,3R)—N-(3-Aminocyclopentylmethyl)nicotinamide

A compound from preparation 193 (58 mg, crude) was dissolved intrifluoroacetic acid (2 mL) and stirred for half an hour. The reactionmixture was evaporated under vacuum and the residue was dissolved inmethylene chloride and filtered through scx column (Bond Elut, 60 cc)and eluted with methanol-ammonia solution (2M) to obtain the titlecompound (quantitative). ESMS: 220 (M+1)⁺, 278 (M+59)⁻.

PREPARATION 195(1S,3R)—N-(3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}cyclopentylmethyl)-nicotinamide

A solution of a compound from preparation 194 (112 mg, 0.51 mmol),2-chloro-6-fluoro phenyl isoxazoyl chloride (210 mg, 0.76 mmol),triethyl amine (0.5 mL), and DMAP (10 mg) dissolved in DMF (5 mL) wasstirred for four hours at rt. The reaction mixture was diluted withethyl acetate (20 mL) and washed water (2×20 mL), brine (2×20 mL), driedover sodium sulfate, filtered and evaporated to obtain the titlecompound (104 mg, 28%, used without purification). ESMS: 455 (M−1)⁻, 515(M+59)⁻.

PREPARATION 196(1S,3R)(3-{[(Furan-2-carbonyl)amino]methyl}cyclopentyl)-carbamic Acidt-butyl Ester

A solution of a compound from preparation 183 (68 mg, 0.31 mmol),2-furoyl chloride (50 mg, 0.38 mmol), triethyl amine (0.5 mL), and DMAP(5 mg) dissolved in DMF (2 mL) was stirred for four hours at rt. Thereaction mixture was diluted with ethyl acetate (20 mL) and washed withwater (2×20 mL), brine (2×20 mL), dried over sodium sulfate, filteredand evaporated to obtain the title compound (105 mg, crude, used withoutpurification) ESMS: 309 (M+1)⁺, 343 (M+35)⁻.

PREPARATION 197 (1S,3R)-Furan-2-carboxylic Acid(3-aminocyclopentylmethyl)-amide

A compound from preparation 196 (105 mg, crude) was dissolved intrifluoroacetic acid (2 mL) and stirred for half an hour. The reactionmixture was evaporated under vacuum and the residue was dissolved inmethylene chloride and filtered through SCX (Bond Elut, 60 cc) columnand eluted with methanol-ammonia solution to obtain the title compound(94 mg, quantitative). ESMS: 209 (M+1)⁺.

PREPARATION 198(1S,3R)-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylicAcid(3-{[(furan-2-carbonyl)amino]methyl}-cyclopentyl)amide

A solution of a compound from preparation 197 (94 mg, 0.51 mmol),2-chloro-6-fluoro phenyl isoxazoyl chloride (185 mg, 0.67 mmol),triethyl amine (0.5 mL), and DMAP (10 mg) dissolved in DMF (5 mL) wasstirred for four hours at rt. The reaction mixture was diluted withethyl acetate (20 mL) and washed water (2×20 mL), brine (2×20 mL), driedover sodium sulfate, filtered and evaporated to obtain the titlecompound (147 mg, crude, quantitative, used without purification). ESMS:446 (M+1)⁺, 504 (M+59)⁻.

PREPARATION 199(1S,3R){3-[(3,4,5-Trimethoxybenzoylamino)methyl]cyclopentyl}carbamicAcid t-butyl Ester

A solution of a compound from preparation 183 (68 mg, 0.31 mmol),3,4,5-trimethoxy benzoyl chloride (88 mg, 0.38 mmol), triethyl amine(0.5 mL), and DMAP (10 mg) dissolved in DMF (2 mL) was stirred for fourhours at rt. The reaction mixture was diluted with ethyl acetate (20 mL)and washed with water (2×20 mL), brine (2×20 mL), dried over sodiumsulfate, filtered and evaporated to obtain the title compound (130 mg,crude, used without purification). ESMS:409 (M+1)⁺, 443 (M+35)⁻.

PREPARATION 200(1S,3R)—N-(3-Aminocyclopentylmethyl)-3,4,5-trimethoxybenzamide

A compound from preparation 199 (130 mg, crude) was dissolved intrifluoroacetic acid (2 mL) and stirred for half an hour at rt. Thereaction mixture was evaporated under vacuum and the residue wasdissolved in methylene chloride and filtered through SCX (Bond Elut, 60cc) column and eluted with methanol-ammonia solution (2M) to obtain thetitle compound (82 mg, 83%). ESMS: 309 (M+1)⁺, 367 (M+59)⁻.

PREPARATION 201(1S,3R)-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylicAcid{3-[(3,4,5-trimethoxybenzoylamino)methyl]cyclopentyl}amide

A solution of a compound from preparation 200 (82 mg, 0.26 mmol),2-chloro-6-fluoro phenyl isoxazoyl chloride (109 mg, 0.39 mmol),triethylamine (0.5 mL), and DMAP (10 mg) dissolved in DMF (5 mL) wasstirred for four hours at rt. The reaction mixture was diluted withethyl acetate (20 mL) and washed water (2×20 mL), brine (2×20 mL), driedover sodium sulfate, filtered and evaporated to obtain the titlecompound (89 mg, 62%, used without further purification). ESMS: 546(M+1)⁺, 604 (M+59)⁻.

PREPARATION 202(1S,3R)[3-(3(Benzyloxycarbonylaminomethyl)cyclopentyl]carbamic Acidt-butyl Ester

A solution of a compound from preparation 183 (1.3 g, 6 mmol), CBZchloride (1.2 g, 7 mmol), triethyl amine (1 mL), and DMAP (50 mg)dissolved in DCM (50 mL) was stirred for four hours at rt. The reactionmixture was diluted with ethyl acetate (20 mL) and washed with water(2×20 mL), brine (2×20 mL), dried over sodium sulfate, filtered andevaporated to obtain the title compound (2.0 g, crude). ESMS: 349(M+1)⁺, 407 (M+59)⁻.

PREPARATION 203 (1S,3R)(3-Aminocyclopentylmethyl)carbamic Acid BenzylEster

A compound from preparation 202 (2.00 g, crude) was dissolved intrifluoroacetic acid (10 mL) and DCM (10 mL) and stirred for half anhour at rt. The reaction mixture was evaporated under vacuum and theresidue was dissolved in DCM and filtered through SCX (Bondesil, 20 g)column and eluted with methanol-ammonia solution (2M) to obtain thetitle compound (550 mg, 38%). ESMS: 249 (M+1)⁺.

PREPARATION 204(1S,3R)(3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}cyclopentylmethyl)carbamicAcid Benzyl Ester

A solution of a compound from preparation 203 (500 mg, 2 mmol),2-chloro-6-fluorophenyl isoxazoyl chloride (600 mg, 2.2 mmol),triethylamine (1. mL), and DMAP (100 mg) dissolved in DMF (10 mL) wasstirred for four hours at rt. The reaction mixture was diluted withethyl acetate (20 mL) and washed water (2×20 ML), brine (2×20 mL), driedover sodium sulfate, filtered, evaporated and chromatographed (Sicolumn, 12×2.5 inches, gradient −10% to 50% ethyl acetate in hexanes) toobtain the title compound (355 mg, 36%). ESMS: 486 (M+1)⁺, 544 (M+59)⁻.

PREPARATION 205(1S,3R)(3-{[2-(3,4,5-Trimethoxyphenyl)acetylamino]methyl}-cyclopentyl)carbamicAcid t-butyl Ester

A solution of a compound from preparation 183 (1 g, 4.6 mmol),3,4,5-trimethoxy phenylaceticacid (1.5 g, 6.9 mmol), EDC (1.3 g, 6.9mmol) and DMAP (100 mg) dissolved in DCM (20 mL) was stirred overnightat rt. The reaction mixture was washed with water (2×20 mL), brine (2×20mL), dried over sodium sulfate, filtered, and evaporated to obtain thetitle compound (1.5 g, crude). ESMS: 423 (M+1)⁺, 481 (M+59)⁻.

PREPARATION 206(1S,3R)—N-(3-Aminocyclopentylmethyl)-2-(3,4,5-trimethoxy-phenyl)acetamide

A compound from preparation 205 (1.5 g) was dissolved and stirred in asolution of hydrogen chloride in acetic acid(20 mL, 1M) for half an hourat rt. The reaction mixture was evaporated and the residue wastriturated with ether to obtain the title compound (1.1 g, used withoutfurther purification). ESMS:323(M+1)⁺, 357 (M+35)⁻.

PREPARATION 207(1S,3R)-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid(3-{[2-(3,4,5-trimethoxyphenyl)acetyl-amino]methyl}cyclopentyl)amide

A solution of a compound from preparation 206 (1 g, 3.1 mmol),2-chloro-6-fluoro phenyl isoxazoyl chloride (850 mg, 3.1 mmol),triethylamine (1 mL), and DMAP (100 mg) dissolved in DCM (20 mL) wasstirred for four hours at rt. The reaction mixture was washed with water(2×20 mL), brine (2×20 mL), dried over sodium sulfate, filtered,evaporated and chromatographed (Si column, 15×6 cm, 50% ethyl acetate inhexane) to obtain the title compound (1.2 g, 70%). ESMS: 486 (M+1)⁺, 544(M+59)⁻.

PREPARATION 208(1S,3R)[3-({[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole4-carbonyl]amino}methyl)cyclopentyl]carbamicAcid t-butyl Ester

A mixture of a compound from preparation 183 (215 mg, 1 mmol), 2-chloro,6-fluoro phenyl isoxazoyl chloride (300 mg, 1.1 mmol), triethyl amine(0.1 mL) and DMAP (20 mg) dissolved in DMF (5 mL) was stirred overnightat r.t. The reaction mixture was diluted with ethyl acetate (25 mL) andwashed with HCl (1M, 2×10 mL), water (2×10 mL), brine (2×10 mL), driedover sodium sulfate, filtered, and evaporated to yield the titlecompound (400 mg, 88%, crude). ESMS: 452 (M+1)⁺.

PREPARATION 209[3-({[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}methyl)cyclopentyl]carbamicAcid t-butyl Ester

A mixture of a compound from preparation 176 (640 mg, 2.9 mmol),2-chloro, 6-fluoro phenyl isoxazoyl chloride (1.22 g, 4.4 mmol),triethyl amine (0.5 mL) and DMAP (50 mg) dissolved in DCM (50 mL) wasstirred overnight at rt. The reaction mixture was washed with HCl (1M,2×10 mL), water (2×10 mL), brine (2×10 mL), dried over sodium sulfate,filtered, and evaporated to yield the title compound (1.5 g, crude,quantitative).

ESMS: 452 (M+1)⁺.

PREPARATION 210 N-(3-aminocyclohexyl)(t-butoxy)carboxamide

To 1,3 diaminocyclohexyl (20.0 g, 175 mmol) in 400 mL CHCl₃ at 0° C. wasadded di-t-butyldicarbonate (7.65 g, 35.0 mmol), which was dissolved in100 mL CHCl₃, poured rapidly. The ice bath was removed and after 0.5 h,the reaction mixture was washed with saturated NaHCO₃ (3×150 mL)andwashed with brine (2×150 mL). The organics were concentrated to give(cis and trains, 2:1) a crude clear oil (7.50 g, 100%). The crudeproduct was used without purification.

PREPARATION 211 and 212N-((1S,3S)-3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonyamino}cyclohexyl)(t-butoxy)carboxamideN-((3S,1R)-3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonyamino}cyclohexyl)(t-butoxy)carboxamide

To the crude oil from preparation 210 (7.50 g, 35.0 mmol) in 75 mLanhydrous CH₂Cl₂ at 0° C. was added Et₃N (7.32 mL, 52.5 mmol) followedby 3-(6-chloro-2-fluorophenyl)-5-methylisoxazole4-carbonyl chloride(10.01 g, 38.5 mmol). After 5 min. the ice bath was removed and thereaction stirred for an additional 25 minutes. The reaction was dilutedwith 300 mL CH₂Cl₂ and washed with saturated NaHCO₃ (100 mL). Theorganics were dried over Na₂SO₄, filtered and concentrated until aprecipitate formed. The precipitate was filtered and the filtrate wasconcentrated a little more to give more precipitate, which was filtered.A total of 8.5 g (54%) of preparation 209 was obtained. The filtrate wasconcentrated and chromatographed with 20-30% EtOAc in hexanes to give3.78 g (24%) of preparation 210.

ESIMS m/e 451 ³⁵Cl (M⁺+1) and 453 ³⁷Cl (M⁺+1).

ESIMS m/e 452 ³⁵Cl (M⁺+1) and 454 ³⁷Cl (M⁺+1).

PREPARATION 213Cis-3-(amino)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexaneHydrochloride

To Example 495 (0.500 g, 1.16 mmol) at 0° C. was added 4M HCl in dioxane(5 mL) to give a suspension. The reaction was sonicated at r.t. for 2min., then stirred at r.t. for 45 minutes. A yellow solid was obtained(0.411 g, 96%). ESIMS m/e 332 ³⁵Cl (M⁺+1) and 334 ³⁷Cl (M⁺+1).

PREPARATION 214 d,1-trans-Octahydroquinolin-2-one

Following the literature procedure of Morzycki et al (Heterocycles,(1995), 41 (12), 2729-2736) 3,4,5,6,7,8-hexahydro-1H-quinolin-2-one (100mg, 0.66 mmol) in dioxane (10 ml) with trifluoroacetic acid (0.042 ml,catalytic) was treated with NaCNBH₃ (0.67 g, 10.8 mmol), and stirred for18 hr at RT. The mixture was then diluted with EtOAc and washed withdilute HCl (0.1 N). Additional EtOAc extrac-tions (2×) were thencombined with the first, and then treated with sat'd bicarbonate, brine,dried over Na₂SO₄, filtered and concentrated to afford the mainly transproduct (98 mg, ˜5:1). MS (+ES) 154 (M+H)+.

PREPARATION 215 3-(2-Amino-trans-cyclohexyl)propionic Acid Methyl EsterHydrochloride

A compound from preparation 214 (1 g, 6.4 mmol) was dissolved inmethanol (100 mL) and conc. HCl (10 ML) and refluxed for 20 h. Thesolvents were removed under vacuum to obtain the title compound (1.05 g,88%). ESMS: 186 (M)⁺, 187 (M+1)⁺.

PREPARATION 2163-(2-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}trans-cyclohexyl)propionicAcid Methyl Ester

To a solution of a compound from preparation 215 (1 g, 4.5 mmol)dissolved in DMF (50 mL), was added 2-chloro-6-fluorophenyl isoxazoylchloride (1.23 g, 4.5 mmol), triethyl amine (10 mL) and DMAP (100 mg)and stirred overnight at rt. The reaction mixture was diluted with ethylacetate (100 mL) and washed with 1M HCl (2×50 mL), water (2×50 mL),brine (2×50 mL), dried over sodium sulfate, filtered and evaporated toyield 1.9 g. ESMS: 423 (M+1)+, 481 (M+Ac)−.

PREPARATIONS 217 and 218 Separation of Preparation 216 into Enantiomers

Preparative separation into enantiomers was achieved by columnchromatography over a Chiralpak AD column using 40% isopropyl alcohol inheptane and 0.2% dimethylethylamine. Thus, the first enantiomer thateluted was designated preparation 217 (Isomer 1), and the second,preparation 218 (Isomer 2).

PREPARATION 2193-(2-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}trans-cyclohexyl)propionicacid

A solution from preparation 217 (0.127 g, 0.3 mmol) in THF (5 mL) wastreated with a 0.5 M soln of LiOH in water (3 mL). The sol'n was stirredat r.t. for 5 hr. The reaction was diluted with water (3 mL) and washedwith EtOAc (2×5 mL). The pH of the aqueous was adjusted to ˜3 with 0.1 MHCl and extracted with EtOAc (4×5 mL). The organic extractions were thenwashed with brine (2×5 mL), dried over sodium sulfate and the solventremoved to afford 0.095 g (80%) as a white solid. MS (ES+) m/z 409.0(M+W)⁺, (ES−) m/z 407.0 (M−H)⁻.

PREPARATION 2203-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic Acid{2-[2-(3,4,5-trimethoxyphenylcarbamoyl)ethyl]trans-cyclohexyl}amide

A sol'n from preparation 219 (0.095 g, 0.23 mmol) and EDC (0.115 g, 0.6mmol) in DMF (25 mL) was treated with 3,4,5 trimethoxyaniline (0.11 g,0.6 mmol). A catalytic amount of DMAP (4 mg, 0.03 mmol) was also added.The reaction mixture was stirred at r.t. overnight. The reaction wasdiluted in EtOAc (100 mL) and washed with 5% citric acid sol'n (3×50mL), water (2×50 mL), and dried over sodium sulfate. The solvent wasremoved in vacuo to afford a crude brown oil which was purified by aVarian Bond Elut SI column (10 g) with an eluting solvent of 1:1hexanes:EtOAc. The solvent was removed in vacuo to afford 0.072 g (54%)as an off white solid. MS (ES+) m/z 574.0 (M+H)⁺, (ES−) m/z 572.1(M−H)⁻, 632.1 (M⁺CH₃COO⁻)⁻.

PREPARATION 221 d,1-cis-Octahydroquinolin-2-one

2-Nitrocinnamic acid (17 g, 82 mmol) was dissolved in acetic acid (120ml) and treated with PtO₂ (10 g) and H₂ (3 atm) for 24 hr at 60° C. Thecrude reaction was then cooled to r.t., filtered and concentrated. Thematerial was then diluted with EtOAc, and sat'd bicarbonate. Afterreextraction of the aqueous phase with EtOAc (2×), the combined organicswere washed with brine, dried over Na₂SO₄, filtered and concentrated toafford a 13:1 mixture of cis/trans product (10 g, 80%). Clean cis isomereventually crystallized from residual solvent. MS (+ES) 154 (M+H)+.

PREPARATION 222 3-(2-Amino-cis-cyclohexyl)propionic Acid Methyl EsterHydrochloride

A solution of a compound from preparation 221 (4.4 mg, 28.9 mmol) inmethanol (50 mL) was treated with conc. HCl (10 mL) and refluxedovernight. The reaction mixture was evaporated to yield the titlecompound (7 g, crude, quantitative). ESMS+: 186 (M+1).

PREPARATION 2233-(2-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}-cis-cyclohexyl)propionicAcid Methyl Ester

A compound from preparation 222 (7 g, 0.038 mmol) was dissolved inCH₂Cl₂ (100 mL) and treated with methyl isoxazoyl chloride (11 g, 0.04mmol) in presence of triethylamine (20 mL) at room temperature for 4 h.The reaction mixture was washed with 1 N HCl (2×100 mL), water (2×100mL), brine (2×100 mL), dried over sodium sulfate, filtered andevaporated to give the title compound (crude gum, 10 g, 62%).

ESMS+: 430 (M), 424 (M+1).

PREPARATION 2243-(2-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}-cis-cyclohexyl)propionicAcid

A solution of a compound from preparation 223 (8.5 g, 20 mmol) dissolvedin THF (200 mL) and LiOH (100 mL, 0.5 M solution) was stirred for 2 h atr.t. The reaction was diluted with water (50 mL) and washed with EtOAc(2×100 mL). The alkaline aqueous solution was acidified to pH 1 withconc. HCl and extracted with EtOAc (3×200 mL). The organic extract waswashed with brine, dried over sodium sulfate, filtered and evaporated toyield a white solid (8 g, 97%). ESMS+: 409 (M+1).

PREPARATION 2253-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid{2-[2-(3,4,5-trimethoxyphenylcarbamoyl)ethyl]-cis-cyclohexyl}amide

A solution of a compound from preparation 224 (1 g, 2.4 mmol), EDC (955mg, 5 mmol), trimethoxyaniline (915 mg, 5 mmol), and DMAP (50 mg,catalytic) in DMF (50 mL) was stirred at r.t. overnight. The reactionmixture was diluted with EtOAc (200 mL) and washed with dil. HCL (1 M,3×100 mL), water (3×100 mL), brine (2×100 mL), dried over sodiumsulfate, filtered and evaporated to give the title compound (1.3 g,97%).

ESMS+: 574 (M), 576 (+2).

PREPARATION 2273-(2-{[5-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carbonyl]amino}cyclohexyl)propionicAcid Methyl Ester

5-(6-Chloro-2-fluorophenyl)-3-methylisoxazole-4-carboxylic acid (0.4mmol) was prepared as described previously, and added to a MeCl₂solution (10 ml) of a compound from preparation 222 (222 mg, 1.2 eq)followed by Et₃N (133 ml, 0.96 mmol) and DMAP (10%) at r.t. Acylationwas allowed to proceed for 18 h. Crude product was obtained by dilutionof the reaction mixture with MeCl₂ and 0.1 N HCl, transferring to aseparatory funnel. The organic phase was then washed with sat'dbicarbonate, brine, then dried over Na₂SO₄. Filtration and concentrationprovided crude product, which was then purified using a Bond-Elut Sicolumn (1 g, 1:1 hex/EtOAc) to generate the title compound (86 mg, 51%).MS (+ES) m/z 422.9/424.9 (M+H).

PREPARATION 2273-(2-{[5-(2-Chloro-6-fluoro-phenyl)-3-methyl-isoxazole-4-carbonyl]-amino}-cyclohexyl)-propionicAcid

To a solution of the compound from 226 (86 mg, 0.2 mmol) in THF (5 ml)was added 2 ml 0.5M aq. LiOH (5 eq), dropwise at r.t. Hydrolysis wascomplete at 2.5 hr. After dilution with water and EtOAc, the contentswere transferred to a separatory funnel, where addition of enough 1N HClwas added to maintain pH 2. The aqueous phase was back extracted 3 timeswith additional solvent, and the combined organics were then washed withbrine, dried over Na₂SO₄. Filtration and concentration afforded cleanacid, 80 mg (97%), which was used without further purification. MS (+ES)m/z 408.9/410.9 (M+H).

PREPARATION 2285-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylicAcid-{2-[2-(3,4,5-trimethoxyphenylcarbamoyl)ethyl]-cyclohexyl}amide

To the acid from preparation 227 (40 mg, 0.1 mmol) in DMF (2 ml) wasadded catalytic amount of DMAP (10%, 1 mg), followed by EDC.HCl (20.6mg, 0.11 mmol) and 3,4,5-trimethoxyaniline (20.1 mg, 0.11 mmol) at r.t.After 18 hr, the reaction was transferred to a separatory funnel anddiluted with EtOAc and 1N NaOH (aq. pH 9-10). The aqueous phase wasextracted 3 times, and combined EtOAc fractions were then washedsequentially with 1 N HCl, sat'd bicarbonate, brine, and then dried overNa₂SO₄. After filtration and concentration, crude amide was obtained (33mg). Starting material (7 mg) was also recovered from the aqueousfraction upon acidification and standard work-up. The crude product wasthen chromatographically purified (Bond-Elut Silica column, 1 g, 2:1EtOAc/hexanes) to afford clean amide (48 mg, 50%). MS (ES+) 573.9, 575.9(M+H)+.

PREPARATION 229 Methyl 3-(2-aminocyclohexyl)propanoate Hydrochloride

A solution of a compound from preparation 163 (4.4 mg, 28.9 mmol) inmethanol (50 mL) was treated with conc. HCl (10 mL) and refluxedovernight. The reaction mixture was evaporated to yield the titlecompound (7 g, crude, quantitative). ESMS⁺: 186 (M+1).

PREPARATION 230 Methyl3-(2-{[3-(6-chloro-2-fluorophenyl)-5-methylisoxazol4-yl]carbonylamino}cyclohexyl)propanoate

A compound from preparation 229 (7 g, 0.038 mmol) was dissolved inmethylene chloride (100 mL) and treated with methyl isoxazoyl chloride(11 g, 0.04 mmol) in presence of triethylamine (20 mL) at roomtemperature for four hours. The reaction mixture was washed with 1 N HCl(2×100 mL), water (2×100 mL), brine (2×100 mL), dried over sodiumsulfate, filtered and evaporated to give the title compound (crude gum,10 g, 62%). ESMS+: 430 (M), 424 (M+1).

PREPARATION 2313-(2-{[3-(6-chloro-2-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)propanoicAcid

A solution of the ester from preparation 230 (8.5 g, 20 mmol) dissolvedin THF (200 mL) and LiOH (100 mL, 0.5 M solution) was stirred for 2 h atrt. LiOH solution was diluted with water (50 mL) and washed with ethylacetate (2×100 mL). The alkaline aqueous solution was acidified to pH 1with conc. HCl and extracted with ethyl acetate (3×200 mL). The ethylacetate extract was washed with brine, dried over sodium sulfate,filtered and evaporated to yield a white solid (8 g, 97%). ESMS+: 409(M+1).

PREPARATION 2323-(2-{[3-(6-chloro-2-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)-N-(3,4,5-trimethoxyphenyl)propanamide

A solution of acid from preparation 231 (1 g, 2.4 mmol), EDC (955 mg, 5mmol), trimethoxyaniline (915 mg, 5 mmol), and DMAP (50 mg, catalytic)in DMF (50 mL) was stirred at r.t. overnight. The reaction mixture wasdiluted with ethyl acetate (200 mL) and washed with dil. HCL (1 M, 3×100mL), water (3×100 mL), brine (2×100 mL), dried over sodium sulfate,filtered and evaporated to give the title compound (1.3 g, 97%).

ESMS +: 574 (M), 576 (M+2).

PREPARATION 233 6-Fluoropyridine-2-carboxylic Acid

To a heterogeneous solution of 2-fluoro-6-methyl-pyridine (9.65 g, 86.8mmol) in water (400 mL) was added potassium permanganate (31.6 g, 200mmol), and the reaction was heated to approximately 100° C. After 30minutes, additional potassium permanganate (16.5 g, 104 mmol) was added,and the reaction heated at 100° C. overnight. The reaction was filteredthrough celite to remove manganese salts. The mother liquor was washedwith ethyl ether (200 mL×3), neutralized to pH 7, and concentrated downto approximately 100 mL total volume. The aqueous solution was acidifiedto pH 2 with concentrated HCl and extracted with ethyl acetate, followedby 20% i-PrOH/CHCl₃ (×3). The combined organic layers were dried overMgSO₄ and concentrated. The solids were suspended in chloroform,sonicated, then filtered to remove remaining side products. The motherliquor was concentrated to give 5.47 g as a white crystalline solid, 45%yield. ¹H NMR: consistent with structure. MS (ion spray) 140 (M⁻).

PREPARATION 234 6-Methoxy-pyridine-2-carboxylic Acid

To 6-hydroxypicolinic acid (1.39 g, 10.0 mmol) in toluene (35 mL) wasadded silver oxide (2.43 g, 10.5 mmol) and the mixture was stirred for30 minutes. To the reaction was added iodomethane (1.31 mL, 21.0 mmol),and the reaction was heated to reflux overnight. The reaction wasfiltered over celite and concentrated to give 1.45 g of the methyl esteras a yellow solid. The resulting solid was dissolved in tetrahydrofuran(50 mL), and added to a solution of 5N NaOH (20 mL, 100 mmol) and water(5 mL). After one hour, the reaction was acidified to pH 3 with 5N HCland concentrated. To the resulting white solids was added 20% MeOH/CHCl₃and the mixture was sonicated for 20 minutes. The mixture was filtered,and the mother liquor was dried over MgSO₄ and concentrated to give 1.33g of the title compound as a white solid, 87% yield.

¹H NMR: consistent with structure. MS (ion spray) 152 (M⁻).

PREPARATION 235 5-Methoxy-nicotinic Acid

To sodium hydride (0.42 g, 10.5 mmol, washed with hexanes ×3) indimethylformamide (15 mL) was added 5-hydroxy-nicotinic acid methylester (1.53 g, 10.0 mmol) in dimethylformamide (10 mL). After threeminutes, iodomethane (0.65 mL, 10.5 mmol) was added dropwise whilestirring at room temperature. After 1 h, the reaction was quenched withmethanol and concentrated to a brown oil. The solution was dissolved in20% isopropanol/chloroform, washed with saturated aqueous sodiumbicarbonate solution, brine (×3), dried over magnesium sulfate andconcentrated to give 1.46 g of 6-methoxynicotinic acid methyl ester. Theresulting oil was dissolved in tetrahydrofuran (50 mL), and added to asolution of 5N NaOH (20 mL, 100 mmol) and water (5 mL). After 30minutes, an additional 25 mL of 5N NaOH was added to the solution. Afterone hour, the reaction was acidified to pH 3 with 5N HCl andconcentrated. To the resulting white solids was added 20% MeOH/CHCl₃ andthe mixture was sonicated for 20 minutes. The mixture was filtered, andthe mother liquor was dried over MgSO₄ and concentrated to give 1.38 gas a light yellow solid, 90% yield.

¹H NMR: consistent with structure. MS (ion spray) 152 (M⁻).

PREPARATION 236N-{3-[3-(1-Aminoethylidene)-5-chloro-2,4-dioxo-3,4-dihydro-2H-quinolin-1-yl]-cyclohexylmethyl}benzamide

A compound from Example 125 (0.05 g, 0.1 mmol) and Mo(CO)₆ (0.3 g, 1.1mmol) were combined in a solution of ACN (5 mL) and water (1 mL). Thereaction mixture was heated to 60° C. while stirring. After 3 hr ofstirring the reaction was complete. The reaction was concentrated to adark brown solid under vacuum. The solid was diluted in CH₂Cl₂ (1 mL)and purified by passing through a Varian Bond Elut SI column (5 g). Theproduct was eluted with 2% MeOH in CH₂Cl₂. The solvent was removed invacuo to afford 0.041 g (82%) of the title compound as a light brownsolid.

MS (ES+) m/z 452.0 (M+H)⁺, (ES−) 450.0 (M−H)⁻.

PREPARATION 237{3-[3-(1-Aminoethylidene)-5-chloro-2,4-dioxo-3,4dihydro-2H-quinolin-1-yl]-cyclohexylmethyl}carbamicAcid Benzyl Ester

A compound from Example 498 (0.25 g, 0.5 mmol) and Mo(CO)₆ (1.35 g, 5.2mmol) were combined in a solution of ACN (25 mL) and water (5 mL). Thereaction mixture was heated to 60° C. while stirring. After stirringovernight the reaction was complete. The reaction was concentrated to adark brown solid under vacuum. The solid was diluted in CH₂Cl₂ (10 mL)and the solid material was filtered by passing through Celite. Theyellow filtrate was purified by silica gel column chromatography using50% EtOAc in CH₂Cl₂ to elute the product. The solvent was removed invacuo to afford 0.24 g (98%) of the title compound as a light yellowsolid. MS (ES+) m/z 481.9 (M+H)⁺, (ES−) 479.9 (M−H)⁻.

PREPARATION 238N-}3-[3-(1-Aminoethylidene)-5-chloro-2,4-dioxo-3,4-dihydro-2H-quinolin-1-yl]-cyclohexylmethyl}nicotinamide

A compound from Example 126 (0.02 g, 0.04 mmol) and Mo(CO)₆ (0.13 g, 0.5mmol) were combined in a solution of ACN (5 mL) and water (1 mL). Thereaction mixture was heated to 60° C. and stirred for 2 hr. The reactionwas concentrated to a dark brown solid under vacuum. The solid wasdiluted in CH₂Cl₂ (10 mL) and purified by passing directly through aBond-Elut cation exchange column. The product was eluted with 2M Ammoniain MeOH. The brown liquid was filtered using a Gelman Nylon Acrodisc toafford a yellow solution. The solvent was removed in vacuo to afford0.018 g (90%) of the title compound as a white solid. MS (ES+) m/z 452.9(M+H)⁺, (ES−) m/z 450.8 (M−H)⁻, 510.9 M+CH3COO⁻)⁻.

PREPARATION 239N-{3-[3-(1-Aminoethylidene)-5-chloro-2,4-dioxo-3,4-dihydro-2H-quinolin-1-yl]-cyclohexylmethyl}-6-fluoronicotinamide

A compound from Example 149 (0.05 g, 0.1 mmol) and Mo(CO)₆ (0.3 g, 1.1mmol) were combined in a solution of ACN (5 mL) and water (1 mL). Thereaction mixture was heated to 60° C. while stirring. After 3 hr ofstirring the reaction was complete. The reaction was concentrated to adark brown solid under vacuum. The solid was diluted in CH₂Cl₂ (1 mL)and purified by passing through a Varian Bond Elut SI column (5 g). Theproduct was eluted with 2% MeOH in CH₂Cl₂. The solvent was removed invacuo to afford 0.041 g (82%) of the title compound as a light brownsolid.

MS (ES+) m/z 452.0 (M+H)⁺, (ES−) 450.0 (M−H)³¹ .

PREPARATION 240N-{3-[5-Chloro-3-(1-hydroxy-ethylidene)-2,4-dioxo-3,4-dihydro-2H-quinolin-1-yl]-cyclohexylmethyl}benzamide

A compound from preparation 236 (0.05 g, 0.11 mmol) was stirred in asolution of acetonitrile (10 mL) and water (1 mL). The solution wastreated with p-toluenesulfonic acid (0.01 g, 0.05 mmol). The reactionwas heated to reflux and stirred overnight. The reaction wasconcentrated to a solid and diluted in EtOAc (50 mL). The organic waswashed with sat'd sodium bicarbonate (2×10 mL), brine (2×10 mL), anddried over sodium sulfate. The solvent was removed to yield a crudesolid that was purified using a chromatotron with a silica gel plate.The product was eluted with 50% EtOAc in CH₂Cl₂. The solvent was removedto afford 0.032 g (64%) of the title compound as an off-white solid. MS(ES+) m/z 452.9 (M+H)⁺, (ES−) 450.9 (M−H)⁻.

PREPARATION 241 (3-Aminocyclohexylmethyl)carbamic Acid Benzyl Ester

S-Amino enantiomer of a compound from preparation 104 (0.28 g, 0.77mmol) was treated with HCl in HOAc (1.0M, 2 mL) under N₂. After 20 minof stirring at r.t., the reaction was complete. The crude was thenconcentrated to a solid using CAN to azeotrope the solvent. The whitesolid was taken up in ether and filtered. The white solid weighed 0.19 g(95%) and was in good purity. MS (ES+) m/z 263.0 (M+H)⁺.

PREPARATION 242 t-Butylaminophenylacetic Acid Methyl Ester

t-Butylamine (9.30 mL, 88.0 mmol) was combined with α-bromophenylaceticacid (5.0 g, 22.0 mmol) and triethylamine (3.40 mL, 22.0 mmol) intetrahydrofuran (200 mL) and the mixture refluxed overnight. The mixturewas then concentrated in vacuo and the residue taken up in 20%isopropanol/chloroform and washed 1× aqueous NaHCO₃, ×2 brine, and driedover sodium sulfate. Concentration left a residue which was loaded ontoa silica gel column and eluted with methanol/chloroform to yield pureamine (1.34 g, 28%) as an oil. MS(ES): (M+1)⁺ 222.2, 223.2 m/z.

PREPARATION 243 t-Butylaminophenylacetic Acid

A compound from preparation 242 (1.32 g, 6.0 mmol) was combined withaqueous 2N sodium hydroxide (20 mL), tetrahydrofuran (5 mL), and ethanol(5 mL) and the mixture stirred overnight at ambient temperature. Themixture was then adjusted to approx. pH 2.5 with aqueous hydrochloricacid and concentrated to dryness in vacuo. The resulting solids werethen slurried and washed with 20% ethanol/ethyl acetate. Concentrationof the filtrate left crude amino acid derivative (0.94 g, 75%) as an offwhite solid which was used without further purification. MS(ES): (M+1)⁺208.2 m/z.

PREPARATION 244 (2,2-Dimethylpropylamino)phenylacetic Acid Methyl Ester

Neopentylamine (5.13 mL, 43.6 mmol) was combined withα-bromophenylacetic acid (5.00 g, 22.0 mmol) and triethylamine (3.65 mL,26.2 mmol) in tetrahydrofuran (60 mL) and the mixture overnight atambient temperature. The mixture was then diluted with ethyl acetate,washed with water, and dried over sodium sulfate. Concentration left aresidue, which was loaded onto a silica gel column and eluted withmethanol/chloroform to yield 3.38 g (66%) of pure amine as an oil.MS(ES): (M+1)⁺ 236.1, 237.1 m/z.

PREPARATION 245 (2,2-Dimethylpropylamino)phenylacetic Acid

An amine from preparation 244 (3.20 g, 13.6 mmol) was combined withaqueous 2N sodium hydroxide (30 mL), tetrahydrofuran (10 mL), andethanol (5 mL) and the mixture stirred overnight at ambient temperature.The mixture was then treated in a manner similar to that in preparation11 which left crude amino acid derivative (0.337 g, 11%) as a whitesolid and was used without further purification. MS(ES): (M+1)⁺ 222.1m/z.

PREPARATION 246 Pyrimidine-5-carboxylic Acid Methyl Ester

A mixture of 5-bromopyrimidine (3.0 g, 18.8 mmol), 1.86 g of1,1′-bis-(diphenylphospino)ferrocene, and 1.15 g of Pd(II)acetate in 40mL of methanol and 40 mL of N,N-dimethylformamide was stirred under 60psi of carbon monoxide at 85° C. for 16 hours. The reaction mixture wasfiltered and partitioned between ether and brine. The aqueous layer wasextracted with ether. Combined organics were washed with brine, driedover sodium sulfate and was concentrated to dryness. The residue wasdissolved in chloroform, filtered through celite and concentrated todryness to yield 1.89 g (73%) of the desired crude product as a tansolid. Crude product was carried on without further purification. MS(ion spray) 123.3 (M-methyl).

PREPARATION 247 Pyrimidine-5-carboxylic Acid

To a solution of a compound from preparation 246, 1.8 g (13.0 mmol) in60 mL of tetrahydrofuran, was added a solution of 3.0 g (130 mmol) oflithium hydroxide in 60 mL of water. The reaction mixture was stirredfor five hours at ambient temperature and was then washed with ether andacidified to pH=1 with 5 N HCl. The resulting solution was extractedwith 20% isopropanol/chloroform. Combined organics were washed withbrine, dried over sodium sulfate, filtered and concentrated to drynessto yield 460 mg (28%) of the desired product as a crude tan oil. Crudeproduct was carried on without further purification. MS (ion spray)123.3 (M−) for desired product.

PREPARATION 248 2-Methoxyisonicotinic Acid Methyl Ester

To a solution of 2-methoxyisonicotinic acid methyl ester, 0.32 g (1.9mmol) in 20 mL of tetrahydrofuran was added 1.9 mL (9.5 mmol) of 5 Nsodium hydroxide in 10 mL of water. The reaction mixture was stirred for2.5 hours at ambient temperature, acidified to pH=3.6 with 5 N HCl andconcentrated to dryness. The residue was slurried in 20%isopropanol/chloroform and filtered. The solid was slurried in ethylacetate and filtered. The combined organics were dried over sodiumsulfate, filtered and concentrated to dryness to give a quantitativeyield of the crude desired product as a white solid. MS (ion spray)154.1 (M+). Crude product was carried on without further purification.

PREPARATION 249 2-Cyano4-methoxypyridine

To a slurry of 4-methoxypyridine N-oxide hydrate, 50 g, in 250 mL ofchloroform was added 20 g of magnesium sulfate. The slurry was stirredfor 1 hour at ambient temperature, then filtered and concentrated todryness. To a solution of the residue, 4-methoxypyridine N-oxide, 43 g(350 mmol) in 350 mL of dichloromethane was added 65 mL (490 mmol) oftrimethylsilylcyanide. The solution was cooled to 10° C. and 45 mL (490mmol) of N,N-dimethylcarbamyl chloride was added dropwise such that thereaction warmed to a gentle reflux. Upon completion of the addition, thereaction mixture was stirred overnight at ambient temperature, thencarefully quenched at 0° C. dropwise with 10% aqueous potassiumcarbonate. The layers were separated and the aqueous layer was extractedwith dichloromethane. The combined organics were washed with brine,dried over sodium sulfate, filtered and concentrated to dryness. Theresidue was triturated with ether. Filtration of the solid provided 31.4g (67%) of the desired product as a white solid. ¹H—NMR is consistentwith structure; MS (ion spray) 135.1 (M+).

PREPARATION 250 4-Methoxypicolinic Acid Hydrochloride

A solution of a compound from preparation 249, 15.0 g (112 mmol) in 100mL of 5 N HCl was refluxed overnight, cooled to ambient temperature andconcentrated to dryness to yield 22 g the desired product as a crude,white solid. MS (ion spray) 153.9 (M+). Crude product was carried onwithout further purification.

PREPARATION 251 6-Methoxynicotinic Acid

To a solution of methyl 6-methoxynicotinate (Avacado), 0.1 g (0.6 mmol)in 5 mL of tetrahydrofuran was added a solution of 1.2 mL of 5 N sodiumhydroxide in 5 mL of water. The mixture was stirred for four hours atambient temperature, acidified to pH=3 with 5 N HCl and concentrated todryness to yield the crude desired compound. MS (ion spray) 154.0 (M+1).The crude product was carried on without further purification.

PREPARATION 252 Dimethylaminophenylacetic Acid Methyl Ester

To a solution of α-bromophenylacetic acid methyl ester, 5.0 g (22.0mmol) in 120 mL of tetrahydrofuran was added 12 mL (88.0 mmol) oftriethylamine and 5.4 g (66.0 mmol) of dimethylamine hydrochloride. Thereaction mixture was heated at 60° C. in a sealed tube for three hours,cooled to ambient temperature and concentrated to dryness. The residuewas partitioned between 20% isopropanol/chloroform and water. Themixture was washed with saturated sodium bicarbonate, washed with brine,dried over sodium sulfate, filtered and concentrated to dryness. Theresidue was purified by chromatography using a methanol/chloroformgradient as eluent and concentrated to dryness to yield 1.86 g (44%) ofthe desired isomer as a yellow oil. MS (ion spray) 193.9 (M+).

PREPARATION 253 Dimethylaminophenylacetic Acid

To a solution of a compound from preparation 252, 60 mg (0.84 mmol) in10 mL of tetrahydrofuran was added a solution of 0.5 mL (2.52 mmol) of 5N sodium hydroxide in 5 mL of water. The mixture was stirred for twohours at ambient temperature then an additional 1 mL (5.04 mmol) of 5 Nsodium hydroxide was added. The reaction mixture was stirred anadditional four hours, acidified to pH=3 with 5 N HCl, and concentratedto dryness to give a quantitative yield of the crude desired mixture ofisomers. Crude product was carried on without further purification. MS(ion spray) 202.1 (M+23(Na)).

PREPARATION 254 Phenylthiomorpholin-4-ylacetic Acid Methyl Ester

To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g(22.0 mmol) in 120 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) oftriethylamine and 6.7 g (66.0 mmol) of thiomorpholine. The reactionmixture was refluxed for four hours, cooled to ambient temperature andconcentrated to dryness. The residue was partitioned between 20%isopropanol/chloroform and water. The mixture was washed with saturatedsodium bicarbonate, washed with brine, dried over sodium sulfate,filtered and concentrated to dryness. The residue was purified bychromatography using a methanol/chloroform gradient as eluent. A secondpurification was performed using chloroform as eluent and wasconcentrated to dryness to yield 5.36 g (97%) of the desired mixture ofisomers as a yellow oil. MS (ion spray) 252.1 (M+).

PREPARATION 255 Phenylthiomorpholin-4-ylacetic Acid

To a solution of a compound from preparation 254, 140 mg (0.56 mmol) in5 mL of tetrahydrofuran was added a solution of 0.6 mL (2.8 mmol) of 5 Nsodium hydroxide in 5 mL of water. The mixture was stirred for two hoursat ambient temperature then an additional 0.5 mL (2.3 mmol) of 5 Nsodium hydroxide was added in mL of water. The reaction mixture wasstirred an additional two hours, acidified to pH=3 with 5 N HCl, andconcentrated to dryness to give a quantitative yield of the crudedesired mixture of isomers. Crude product was carried on without furtherpurification. MS (ion spray) 236.1 (M+23(Na)).

PREPARATION 256 (4-Methylpiperazin-1-yl)phenylacetic Acid Methyl Ester

To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g(22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) oftriethylamine and 7.3 g (66.0 mmol) of 1-methylpiperazine. The reactionmixture was refluxed for three hours, cooled to ambient temperature andconcentrated to dryness. The residue was partitioned between 20%isopropano/chloroform and water. The mixture was washed with saturatedsodium bicarbonate, washed with bane, dried over sodium sulfate,filtered and concentrated to dryness. The residue was purified bychromatography using a methanol/chloroform gradient as eluent. A secondpurification was performed using methanol/chloroform as eluent and wasconcentrated to dryness to yield 5.21 g (95%) of the desired mixture ofisomers as a yellow oil. MS (ion spray) 249.1 (M+).

PREPARATION 257 (4-Methylpiperazin-1-yl)phenylacetic Acid

To a solution of racemic a compound from preparation 256, 200 mg (0.84mmol) in 10 mL of dioxane was added a solution of 200 mg (8.4 mmol) oflithium hydroxide 8 mL of water. The mixture was stirred for six hoursat ambient temperature, was acidified to pH=3 with 5 N HCl, andconcentrated to dryness to give a quantitative yield of the crudedesired mixture of isomers. Crude product was carried on without furtherpurification.

MS (ion spray) 235.14 (M+).

PREPARATION 258 (4-Acetylpiperazin-1-yl)phenylacetic Acid Methyl Ester

To a solution of racemic x-bromophenylacetic acid methyl ester, 5.0 g(22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) oftriethylamine and 8.5 g (66.0 mmol) of 1-acetylpiperazine. The reactionmixture was refluxed for three hours, cooled to ambient temperature andconcentrated to dryness. The residue was partitioned between 20%isopropanol/chloroform and water. The mixture was washed with saturatedsodium bicarbonate, washed with brine, dried over sodium sulfate,filtered and concentrated to dryness. The residue was purified bychromatography using a methanol/chloroform gradient as eluent and wasconcentrated to dryness to give a quantitative yield of the desiredmixture of isomers as a yellow, viscous oil. MS (ion spray) 277.2 (M+).

PREPARATION 259 (4-Acetylpiperazin-1-yl)phenylacetic Acid

To a solution of a racemic compound from preparation 258, 232 mg (0.84mmol) in 10 mL of dioxane was added a solution of 200 mg (8.4 mmol) oflithium hydroxide 8 mL of water. The mixture was stirred for six hoursat ambient temperature, was acidified to pH=3 with 5 N HCl, andconcentrated to dryness to give a quantitative yield of the crudedesired mixture of isomers. Crude product was carried on without furtherpurification.

MS (ion spray) 269.2 (M+Li).

PREPARATION 259 (Indan-2-ylamino)phenylacetic Acid Methyl Ester

To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g(22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) oftriethylamine and 8.8 g (66.0 mmol) of 2-aminoindan. The reactionmixture was refluxed for four hours, cooled to ambient temperature andconcentrated to dryness. The residue was partitioned between 20%isopropanol/chloroform and water. The mixture was washed with saturatedsodium bicarbonate, washed with brine, dried over sodium sulfate,filtered and concentrated to dryness. The residue was purified bychromatography using chloroform as eluent and was concentrated todryness to give a quantitative yield of the desired mixture of isomersas a tan, viscous oil. MS (ion spray) 282.2 (M+).

PREPARATION 260 (Indan-2-ylarmino)phenylacetic Acid

To a solution of a racemic compound from preparation 259, 236 mg (0.84mmol) in 10 mL of dioxane was added a solution of 200 mg (8.4 mmol) oflithium hydroxide 8 mL of water. The mixture was stirred for four hoursat ambient temperature, was acidified to pH=3 with 5 N HCl, andconcentrated to dryness to give a quantitative yield of the crudedesired mixture of isomers. Crude product was carried on without furtherpurification. MS (ion spray) 268.2 (M+1).

PREPARATION 261 Hydroxy-m-tolyl-acetic Acid

To m-methylbenzaldhyde, 21 mL (176 mmol) was added 5 mg of zinc (II)iodide and 23.4 mL (176 mmol) of trimethylsilyl cyanide dropwise. Theresulting solution was stirred overnight at ambient temperature. To thissolution was added 75 mL of 9 N hydrochloric acid. The mixture wasstirred overnight at ambient temperature and was concentrated todryness. The residue was partitioned between water and 20%isopropanol/chloroform and washed with brine, dried over sodium sulfate,filtered and concentrated to dryness. Crude product was recrystallizedfrom chloroform to provide 15 g of a tan solid. NMR analysis indicates a2:1 mixture of product to cyanohydrin intermediate. This mixture wascarried on as is without further purification. MS (ion spray) 165.1(M−1).

PREPARATION 262 (2-Fluoro-phenyl)-hydroxy-acetic Acid

To o-fluorobenzaldhyde, 18.5 mL (176 mmol) was added 5 mg of zinc (II)iodide and 23.4 mL (176 mmol) of trimethylsilyl cyanide dropwise. Theresulting solution was stirred overnight at ambient temperature. To thissolution was added 100 mL of 9 N hydrochloric acid. The mixture wasstirred overnight at ambient temperature, then refluxed overnight. Themixture was then concentrated to dryness. The residue was partitionedbetween water and 20% isopropanol/chloroform and washed with brine,dried over sodium sulfate, filtered and concentrated to dryness. Crudeproduct was recrystallized from chloroform to provide 4.57 g (15%) of atan solid. MS (ion spray) 169.2 (M−).

PREPARATION 263[3-(3-Acetyl-4-amino-5-chloro-2-oxo-2H-quinolin-1-yl)-cyclohexylmethyl]-carbamicAcid Benzyl Ester

A solution of[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-carbamicacid benzyl ester (0.5 g, 1.04 mmol) and Mo(CO)6 (3.0 g, 0.01 mmol) inAcetonitrile (50 mL) and water (5 mL) was heated to 60° C. and stirredovernight. The reaction was concentrated to a solid, diluted in CH₂Cl₂and filtered through Celite to remove the black insoluble material. Thefiltrate was concentrated to a solid and purified using silica gelcolumn chromatography. The product was eluted with 10% EtOAc in CH₂Cl₂.The solvent was removed to afford 0.520 g (quantitative) of product as alight brown oil. MS (ES+) m/z 482.0 (M+H)⁺,(ES−) m/z 479.9 (M−H)⁻, 540.0(M+CH3COO⁻)⁻.

PREPARATION 264N-[3-(3-Acetyl-4-amino-5-chloro-2-oxo-2H-quinolin-1-yl)-cyclohexylmethyl]-6-fluoro-nicotinamide

A solution of Example 420 (0.07 g, 0.15 mmol) and Mo(CO)6 (0.43 g, 1.6mmol) in Acetonitrile (5 mL) and water (1 mL) was heated to 60° C. andstirred overnight. The reaction was concentrated to a solid, diluted inCHCl₃ and filtered through Celite to remove the black insolublematerial. The filtrate was concentrated to a solid and purified usingsilica gel column chromatography. The product was eluted with 80% EtOAcin CHCl₃. The solvent was removed to afford 0.04 g (57%) of product as awhite solid. MS (ES+) m/z 471.1 (M+M)⁺,(ES−) m/z 469.1 (M−H)⁻, 529.1(M+CH3COO⁻)⁻.

PREPARATION 265(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic Acid EthylEster

To a mixture of ethyl3-(2-fluoro-6-iodo-phenyl)-5-methyl-isoxazole-4-carboxylate (0.25 g,0.67 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.067 mmol),and triethylamine (5 ml) under N₂ was added trimethylsilyl cyanide andheated at reflux overnight. The reaction was cooled to room temperature,diluted with H₂O, and extracted with EtOAc (2×). The combined extractswere washed (H₂O then brine), dried (MgSO₄), filtered, and concentrated.Flash chromatography (silica gel, EtOAc/hexanes gradient) gave the titlecompound (0.15 g, 82%). Mass Spectrum (ES+) (m/z) 275.0 [M+1].

PREPARATION 2663-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic Acid

A mixture of a compound from preparation 265 (0.14 g, 0.51 mmol), EtOH(2.5 ml), and 5 N NaOH (0.3 ml, 1.5 mmol) was heated at 50° C. for 1.5h. The reaction was cooled to room temperature, diluted with H₂O, andacidified (conc. HCl) to less than pH 3. The mixture was extracted withEtOAc (2×) and the combined extracts were washed (H₂O then brine), dried(MgSO₄), filtered, and concentrated to give the title compound (0.1 g,80%). This material was used without further purification. Mass Spectrum(ES+) (m/z) 247.0 [M+1].

PREPARATION 267[3-(2-cyano-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-{3-[(phenylcarbonylamino)-methyl]cyclohexyl}carboxamide

To a solution of a compound from preparation 265 (0.1 g, 0.41 mmol) indichloromethane (10 ml) under N₂ was added oxalyl chloride (0.07 ml,0.82 mmol) then DMF (1 drop) and stirred for 2 h. The solution wasconcentrated, redissolved in dichloromethane (5 ml) under N₂, andN-(3-Amino-cyclohexylmethyl)-benzamide (0.114 g, 0.49 mmol) was added.The reaction vessel was submerged in a water bath and triethylamine(0.17 ml, 1.23 mmol) was added dropwise. After 2.5 h of stirring, themixture was diluted with CH₂Cl₂, washed (1.0 NaOH then brine), dried(MgSO₄), filtered, and concentrated. Flash chromatography (silica gel,Acetone/CH₂Cl₂ gradient) gave the title compound (0.119 g, 63%). MassSpectrum (ES+) (m/z) 461.2 [M+1].

PREPARATION 268 (3-Amino-cyclohexylmethyl)-carbamic Acid Benzyl Ester

A solution of [3-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamicacid tert-butyl ester (6 g, 16.6 mmol) in TFA (30 ml) was stirred for1.5 h. The solution was concentrated using benzene to azeotrope, dilutedwith EtOAc, washed (1.0 N NaOH), dried (Na₂SO₄), filtered, andconcentrated to afford the title compound (4.2 g, 97%) as a crude solid.Mass Spectrum (ES+) (m/z) 263.1 [M+1].

PREPARATION 269(3-{[3-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-cyclohexylmethyl)-carbamicAcid Benzyl Ester

In a fashion similar to that described for preparation 267, a compoundfrom preparation 266 (3.05 g, 12.4 mmol), oxalyl chloride (2.16 ml, 24.8mmol), dichloromethane (50 ml), DMF (0.05 ml), a compound frompreparation 268 (4.2 g, 16.1 mmol), dichloromethane (125 ml), andtriethylamine (5.17 ml, 37.2 mmol) gave the title compound (4.6 g, 76%)after flash chromatography (silica gel, acetone/CH2Cl2 gradient).

Mass Spectrum (ES+) (m/z) 491.2 [M+1].

PREPARATION 270 Diphenylmethyl 2-(3-oxocyclohexyl)propane-1,3-dioate(Cis Racemic)

To a solution of LiAlH₄ (6 ml, 6 mmol) under N₂ at 0° C. was added asolution of (S)-1,1′-binaphthol (3.43 g, 12 mmol) in THF (48 ml) andstirred for 30 min. The reaction was warmed to RT. To this was added asolution of sodium salt benzyl malonate in THF which was prepared byreacting benzyl malonate (14.99 ml, 60 mmol), NaH (60% by wt., 0.216 g,5.4 mmol), and THF (60 ml) until all bubbling ceased. Next,cyclohexenone (5.82 ml, 60 mmol) and dibenzlmalonate (1.35 ml, 5.4 mmol)were added and the reaction mixture was stirred overnight. 1.0 N HCl wasadded and extracted with EtOAc (3×). The combined EtOAc layers werewashed (brine), dried (MgSO₄), filtered, and concentrated. Flashchromatography (silica gel, acetone/hexanes gradient) gave the titlecompound (16.17 g, 71%). Mass Spectrum (FIA) (m/z) 381.3 [M+1].

PREPARATION 271 Diphenylmethyl 2-(3-oxocyclohexyl)propane-1,3-dioate(Trans Racemic)

To a −78° C. solution of a compound from preparation 270 (see Arai, T.;Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki, M. Chem. Eur. J.1996, 2, 1368-1372.) (16.15 g, 42.5 mmol) in THF (212.5 ml) under N₂ wasadded L-selectride (46.75 ml at 1.0 M, 46.75 mmol) dropwise and themixture was stirred for 3.5 h at −78° C. EtOAc and H₂O were added andthe mixture was warmed to room temperature. Dilution with more EtOAcfollowed by washing with 1N NaOH, saturated NH₄Cl, brine, drying(MgSO₄), and flash chromatography (silica gel, EtOAc/hexanes gradient)gave the title compound(14.29 g, 88%). Mass Spectrum (FIA) (m/z) 383.3[M+1].

PREPARATION 272 Phenylmethyl 2-(3-hydroxycyclohexyl)acetate (TransRacemic)

A solution of a compound from preparation 271 (19.19 g, 50.2 mmol, LiCl(4.27 g, 100.5 mmol, H₂O (1.81 ml, 100.5 mmol), and DMSO (135 ml) waslowered into a 165° C. oil bath for 2 h then heated at 175° C. for 1.5h. The reaction was cooled to room temperature and diluted with EtOAc.Washing with H₂O and brine, drying (MgSO₄), and flash chromatography(silica gel, EtOAc/hexanes gradient) gave the title compound (9.71 g,78%). 1H NMR: consistent with structure.

PREPARATION 273 Phenylmethyl 2-(3-azidocyclohexyl)acetate (Cis Racemic)

To a solution of a compound from preparation 272 (9.71 g, 39.2 mmol),triphenylphosphine (12.32 g, 41.04 mmol), and hydrazoic acid (30.9 ml,at 1.9 M, 58.7 mmol) in toluene (120 ml) was added DEAD (9.24 ml, 58.7mmol) dropwise and stirred for 72 h. The mixture was diluted with EtOAc,washed with 0.1 N NaOH, H₂O, and brine, dried (MgSO₄), andchromatographed (silica gel, CH₂Cl₂/hexanes gradient) to give the titlecompound (10.0 g, 93%). 1H NMR: consistent with structure.

PREPARATION 274 Phenylmethyl2-{3-[(tert-butoxy)carbonylamino]cyclohexyl}acetate (Cis Racemic)

A mixture of a compound from preparation 273 (10 g, 36.6 mmol), (BOC)₂O(9.57 g, 43.9 mmol), Lindlar's catalyst (3.7 g), and EtOAc (200 ml) wasstirred under an atmosphere of hydrogen gas (balloon) for 24 h, filteredthrough celite, and concentrated. Flash chromatography (silica gel,EtOAc/hexanes gradient) gave the title compound (7.03 g, 55%). MassSpectrum (FD+) (m/z) 347.3 [M⁺]

PREPARATION 275 2-{3-[(t-Butoxy)carbonylamino]cyclohexyl}acetic Acid(Cis Racemic)

In a fashion similar to that described for preparation 266, a compoundfrom preparation 274 (7 g, 20.2 mmol), 2 N NaOH (25 ml, 50 mmol),Dioxane (100 ml) were reacted for 5 h to give the title compound (5.2 g,100%). Mass Spectrum (FD+) (m/z) 257.3 [M⁺].

PREPARATION 276(t-Butoxy)-N-(3-{[(phenylmethoxy)carbonylamino]methyl}cyclohexyl)carboxamide(Cis Racemic)

To a solution of a compound from preparation 275 (2.6 g, 10.1 mmol),Et₃N (2.84 ml, 20.4 mmol) in toluene (100 ml) under N₂ was added DPPA(4.39 ml, 20.4 mmol) and benzyl alcohol (3.13 ml, 30.3 mmol). Thesolution was heated to reflux overnight. The reaction was cooled to roomtemperature, diluted with EtOAc, washed (1.0 N NaOH then brine), dried(MgSO₄), filtered, and concentrated. Flash chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (2.92 g, 80%). 1H NMR:consistent with structure.

PREPARATION 277 N-[3-(Aminomethyl)cyclohexyl](t-butoxy)carboxamide (CisRacemic)

A mixture of a compound from preparation 276 (1 g, 2.76 mmol), 10% Pd/Ccatalyst (0.5 g), and EtOAc (30 ml) was stirred under an atmosphere ofhydrogen gas (balloon) for 18 h, filtered through celite, andconcentrated to give the title compound (0.48 g, 76%), which was takenon without further purification. Mass Spectrum (ES+) (m/z) 229.1 [M+1].

PREPARATION 278N-({3-[(t-Butoxy)carbonylamino]cyclohexyl}methyl)[3-(6-chloro-2-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

To a solution of a compound from preparation 277 (0.48 g, 2.1 mmol) and3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (0.75g, 2.74 mmol) in dichloromethane (20 ml) under N₂ was added dropwisetriethylamine (0.73 ml, 5.25 mmol) and stirred for 4 h. The reaction wasdiluted with dichloromethane, washed (H₂O then brine), dried (MgSO₄),filtered, and concentrated. Flash chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (0.726 g, 74%). MassSpectrum (ES+) (m/z) 366.1 [M−BOC].

PREPARATION 279[5-chloro-3-(6-chloro-2-fluorophenyl)isoxazol-4-yl]-N-{3-[(phenylcarbonylamino)-methyl]cyclohexyl}carboxamide

In a fashion similar to that described for preparation 267,4-carboxy-5-chloro-3-(2-chloro-5-fluorophenyl)isoxazole acid (0.22 g,0.84 mmol), dichloromethane (2 ml), oxalyl chloride (0.15 ml, 1.68mmol), DMF (0.01 ml), dichloromethane (5 ml),N-(3-Amino-cyclohexylmethyl)-benzamide (0.15 g, 0.65 mmol), andtriethylamine (0.35 ml, 2.52 mmol) gave the title compound (0.29 g, 90%)after flash chromatography (silica gel, Acetone/CH2Cl2 gradient). MassSpectrum (ES+) (m/z) 490.1 [M+1].

PREPARATION 280[5-(Diethylamino)-3-(6-chloro-2-fluorophenyl)isoxazol-4-yl]-N-{3-[(phenylcarbonylamino)methyl]cyclohexyl}carboxamide

To a solution of a compound from preparation 278 (0.1 g, 0.2 mmol) inDMF (2.5 ml) under N₂ was added diethylamine (0.065 ml, 0.63 mmol)j andstirred for 2 h. The reaction was diluted with EtOAc, washed (H₂O thenbrine), dried (MgSO₄), filtered, and concentrated. (0.1 N HCl andbrine), dried (MgSO4), filtered, and concentrated. Flash chromatography(silica gel, acetone/CH2Cl2 gradient) gave the title compound (0.1 g,93%). Mass Spectrum (ES+) (m/z) 527.2 [M+1].

PREPARATION 281[3-(6-Chloro-2-fluorophenyl)-5-pyrrolidinylisoxazol-4-yl]-N-{3-[(phenylcarbonylamino)methyl]cyclohexyl}carboxamide

In a fashion similar to that described for preparation 280, a compoundfrom preparation 279 (0.085 g, 0.17 mmol), DMF (2.5 ml), pyrrolidine(0.14 ml, 1.7 mmol) gave the title compound (0.089 g, 100%) which wastaken on as a crude residue. Mass Spectrum (ES+) (m/z) 525.2 [M+1].

PREPARATION 282[3-(6-Chloro-2-fluorophenyl)-5-(ethylamino)isoxazol-4-yl]-N-{3-[(phenylcarbonyl-amino)methyl]cyclohexyl}carboxamide

In a fashion similar to that described for preparation 280, a compoundfrom preparation 61 (0.085 g, 0.17 mmol), DMF (2.5 ml), ethylamine (0.85ml, 1.7 mmol) gave the title compound (0.085 g, 100%) which was taken onas a crude residue. Mass Spectrum (ES+) (m/z) 499.2 [M+1].

PREPARATION 283[3-(6-Chloro-2-fluorophenyl)-5-ethylthioisoxazol-4-yl]-N-{3-[(phenylcarbonyl-amino)methyl]cyclohexyl}carboxamide

In a fashion similar to that described for preparation 280, a compoundfrom preparation 279 (0.1 g, 0.2 mmol), DMF (2.5 ml), sodiumethanethiolate (0.103 g, 1.0 mmol) gave the title compound (0.85 g,100%) which was taken on as a crude residue. 1H NMR: consistent withstructure.

PREPARATION 2844-(Methoxycarbonyl-phenyl-methyl)-piperazine-1-carboxylic Acidtert-butyl Ester

To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g(22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) ofEt₃N and 12.3 g (66.0 mmol) of BOC-piperazine. The reaction mixture wasrefluxed for 3.5 hours, cooled to rt. and concentrated to dryness. Theresidue was partitioned between 20% isopropanol/chloroform and water.The mixture was washed with saturated NaHCO₃, washed with brine, driedover Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by chromatography using chloroform as eluent and wasconcentrated to dryness to yield 7.73 g (100%) of the desired mixture ofisomers as a colorless oil.

MS (ion spray) 335.2 (M+).

PREPARATION 285 4-(Carboxy-phenyl-methyl)-piperazine-1-carboxylic Acidtert-butyl Ester

To a solution of the compound from preparation 284, 560 mg (1.68 mmol)in 15 mL of dioxane was added a solution of 400 mg (16.8 mmol) oflithium hydroxide in 15 mL of water. The solution was stirred for fivehours at rt. then acidified to pH=3.0 with 5 N HCl and concentrated todryness to give a quantitative yield of the crude desired mixture ofisomers. MS (ion spray) 319.2 (M−). Crude product was carried on withoutfurther purification.

PREPARATION 286 [4-(2-Hydroxy-ethyl)-piperazin-1-yl]-phenyl-acetic AcidMethyl Ester

To a solution of racemic a-bromophenylacetic acid methyl ester, 5.0 g(22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) ofEt₃N and 8 mL (66.0 mmol) of 1-(hydroxyethyl)piperazine. The reactionmixture was refluxed for three hours, cooled to rt. and concentrated todryness. The residue was partitioned between 20% isopropanol/chloroformand water. The mixture was washed with saturated NaHCO₃, washed withbrine, dried over Na₂SO₄, filtered and concentrated to dryness to give aquantitative yield of the desired mixture of isomers as a yellow oil. MS(ion spray) 279.1 (M+).

PREPARATION 287 [4-(2-Hydroxy-ethyl)-piperazin-1-yl]-phenyl-acetic Acid

To a solution of the compound from preparation 286,470 mg (1.68 mmol) in20 mL of dioxane was added a solution of 400 mg (16.8 mmol) of lithiumhydroxide in 20 mL of water. The solution was stirred for 2.5 hours atrt. then acidified to pH=3.0 with 5 N HCl and concentrated to dryness togive a quantitative yield of the crude desired mixture of isomers. Crudeproduct was carried on without further purification.

MS (ion spray) 319.2 (M−).

PREPARATION 288 Phenyl-(4-pyridin-2-yl-piperazin-1-yl)-acetic AcidMethyl Ester

To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g(22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) ofEt₃N and 10 mL (66.0 mmol) of 1-(2-pyridyl)-piperazine. The reactionmixture was refluxed for five hours, cooled to rt. and concentrated todryness. The residue was partitioned between 20% isopropanol/chloroformand water. The mixture was washed with saturated NaHCO₃, washed withbrine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by column chromatography using MeOH/chloroform aseluant and concentrated to dryness to give a quantitative yield of thedesired mixture of isomers as a yellow oil. MS (ion spray) 312.2 (M+).

PREPARATION 289 Piperidin-1-yl-acetic Acid Ethyl Ester

To a solution of bromoethylacetate, 3.3 g (30.0 mmol) in 100 mL oftetrahydrofuran was added 4.2 mL (30.0 mmol) of Et₃N and 9 mL (90.0mmol) of piperidine. The reaction mixture stirred overnight at rt. andwas concentrated to dryness. The residue was partitioned betweenchloroform and saturated aqueous NaHCO₃. The mixture was washed withsaturated NaHCO₃, washed with brine, dried over Na₂SO₄, filtered andconcentrated to dryness to give 4.6 g (89%) of the desired product as atan oil.

MS (ion spray) 172.2 (M+).

PREPARATION 290 Piperidin-1-yl-acetic Acid

To a solution of the compound from preparation 289, 143 mg (0.84 mmol)in 5 mL of dioxane was added a solution of 66 mg (8.4 mmol) of lithiumhydroxide in 5 mL of water. The solution was stirred for three hours atrt. then acidified to pH=2.0 with 5 N HCl and concentrated to dryness togive a quantitative yield of the crude desired product. MS (ion spray)144.1 (M+). Crude product was carried on without further purification.

PREPARATION 291 (4-Methyl-piperazin-1-yl)-acetic Acid Ethyl Ester

To a solution of bromoethylacetate, 3.3 g (30.0 mmol) in 100 mL oftetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonate and3.3 mL (30.0 mmol) of 4-methylpiperazine. The reaction mixture stirredovernight at rt. and was concentrated to dryness. The residue waspartitioned between 20% isopropanol/chloroform and saturated aqueousNaHCO₃. The mixture was washed with saturated NaHCO₃, washed with brine,dried over Na₂SO₄, filtered and concentrated to dryness to give 1.23 g(22%) of the desired product as a tan oil. MS (ion spray) 187.1 (M+).

PREPARATION 292 (4-Methyl-piperazin-1-yl)-acetic Acid

To a solution of the compound from preparation 291, 160 mg (0.84 mmol)in 5 mL of dioxane was added a solution of 66 mg (8.4 mmol) of lithiumhydroxide in 5 mL of water. The solution was stirred for two hours atrt. then acidified to pH=3.0 with 5 N HCl and concentrated to dryness togive a quantitative yield of the crude desired product. MS (ion spray)159.1 (M+). Crude product was carried on without further purification.

PREPARATION 293 (Methyl-phenyl-amino)-acetic Acid Ethyl Ester

To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL oftetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonate and3.25 mL of N-methylaniline. The reaction mixture stirred overnight atrt. and was concentrated to dryness. The residue was partitioned between20% isopropanol/chloroform and saturated aqueous NaHCO₃. The mixture waswashed with saturated NaHCO3, washed with brine, dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by columnchromatography using EtOAc/hexanes as eluent and concentrated to drynessto give 4.74 g (82%) of the desired product as a tan oil. MS (ion spray)194.1 (M+1).

PREPARATION 294 Phenyl-(pyridin-3-yloxy)-acetic Acid Methyl Ester

To a slurry of 3-hydroxypyridine sodium salt, 4.6 g (26.4 mmol) in 200mL of tetrahydrofuran was added 5.0 g (22.0 mmol) ofalpha-bromophenylacetic acid. The reaction mixture was refluxed for twohours, cooled to rt. and concentrated to dryness. The residue waspartitioned between 20% isopropanol/chloroform and water. The mixturewas washed with saturated NaHCO₃, washed with brine, dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by columnchromatography using MeOH/chloroform as eluent and concentrated todryness to give 2.8 g of the desired mixture of isomers as a dark oil.MS (ion spray) 244.1 (M+).

PREPARATION 295 (Pyridin-3-yloxy)-acetic Acid Ethyl Ester

To a solution of 3-hydroxypyridine sodium salt, 6.4 g (36.0 mmol) in 200mL of DMF was added 3.3 mL (30.0 mmol) of bromoethylacetate. Thereaction mixture stirred overnight at rt. and was concentrated todryness. The residue was partitioned between 20% isopropanol/chloroformand saturated aqueous NaHCO₃. The mixture was washed with saturatedNaHCO3, washed with brine, dried over Na₂SO₄, filtered and concentratedto dryness. The residue was purified by column chromatography usingMeOH/chloroform as eluent and concentrated to dryness to give 3.8 g(70%) of the desired product as a tan oil. MS (ion spray) 182.1 (M+).

PREPARATION 296 (Pyridin-3-yloxy)-acetic Acid

To a solution of the compound from preparation 295,(pyridin-3-yloxy)-acetic acid ethyl ester, 300 mg (1.68 mmol) in 15 mLof dioxane was added a solution of 400 mg (16.8 mmol) of lithiumhydroxide in 15 mL of water. The solution was stirred for three hours atrt. then acidified to pH=1.0 with 5 N HCl and concentrated to dryness togive a quantitative yield of the crude desired product. MS (ion spray)154.1 (M+). Crude product was carried on without further purification.

PREPARATION 297 1-tert-Butoxycarbonylamino-cyclohexanecarboxylic Acid

To a slurry of 1-amino-1-cyclohexane-carboxylic acid, 5.0 g (35.0 mmol)in 50 mL of tetrahydrofuran and 50 mL of water was added 14.5 g (105.0mmol) of potassium carbonate, 7.7 g (35.0 mmol) of BOC-anhydride and 5mg of DMAP. The mixture was stirred overnight at rt. and the organicswere evaporated off in vacuo. The aqueous layer was acidified to pH=1with 5 N HCl and extracted with 20% isopropanol/chloroform. The combinedorganics were washed with brine, dried over Na₂SO₄, filtered andconcentrated to dryness to yield 1.83 g (21%) of the desired product asa white oil that solidifies upon standing. MS (IS) 244.2 (M+).

PREPARATION 298 Morpholin-4-yl-acetic Acid Ethyl Ester

To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL oftetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonate and2.6 mL (30.0 mmol) of morpholine. The reaction mixture stirred overnightat rt. and was concentrated to dryness. The residue was partitionedbetween 20% isopropanol/chloroformn and saturated aqueous NaHCO₃. Themixture was washed with saturated NaHCO3, washed with brine, dried overNa₂SO₄, filtered and concentrated to dryness to give 2.75 g (53%) of thedesired product as a tan oil. MS (ion spray) 174.2 (M+).

PREPARATION 299 Morpholin-4-yl-acetic Acid

To a solution of the compound from preparation 298, 150 mg (0.84 mmol)in 10 mL of dioxane was added a solution of 198 mg (8.4 mmol) of lithiumhydroxide in 10 mL of water. The solution was stirred for two hours atrt. then acidified to pH=2.0 with 5 N HCl and concentrated to dryness togive a quantitative yield of the crude desired product. MS (ion spray)146.0 (M+). Crude product was carried on without further purification.

PREPARATION 300 (4-Hydroxy-piperidin-1-yl)-acetic Acid Ethyl Ester

To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL oftetrahydrofuran was added 4.2 g (30.0 mmol) of potassium carbonate and3.0 mL (30.0 mmol) of 4-hydroxypiperidine. The reaction mixture stirredovernight at rt. and was concentrated to dryness. The residue waspartitioned between 20% isopropanol/chloroform and saturated aqueousNaHCO₃. The mixture was washed with saturated NaHCO3, washed with brine,dried over Na₂SO₄, filtered and concentrated to dryness to give 4.65 g(83%) of the desired product as a tan oil. MS (ion spray) 188.0 (M+).

PREPARATION 301 (4-Hydroxy-piperidin-1-yl)-acetic Acid

To a solution of the compound from preparation 300, 158 mg (0.84 mmol)in 10 mL of dioxane was added a solution of 198 mg (8.4 mmol) of lithiumhydroxide in 10 mL of water. The solution was stirred for 1.5 hours atrt. then acidified to pH=2.0 with 5 N HCl and concentrated to dryness togive a quantitative yield of the crude desired product. MS (ion spray)160.1 (M+). Crude product was carried on without further purification.

PREPARATION 302 (2-Oxo-2H-pyridin-1-yl)-acetic Acid Ethyl Ester

To a slurry of sodium hydride, 1.73 g (43.2 mmol) in 100 mL of DMF wasadded 3.4 g (36.0 mmol) of 2-hydroxypyridine. The mixture was stirred 10minutes then added to a solution of 3.3 mL (30.0 mmol) ofbromoethylacetate in 100 mL DMF. The reaction mixture was stirred 72hours at rt. then concentrated to dryness. The residue was partitionedbetween 20% isopropanol/chloroform and water and washed with saturatedaqueous NaHCO₃, washed with brine, dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by columnchromatography using MeOH/chloroform as eluent and concentrated todryness to yield 3.52 g (65%) of the desired product as a colorless oil.¹H—NMR is consistent with structure. MS (ion spray) 182.1 (M+).

PREPARATION 303 (2-Oxo-2H-pyridin-1-yl)-acetic Acid

To a solution of the compound from preparation 302, 152 mg (0.84 mmol)in 10 mL of dioxane was added a solution of 198 mg (8.4 mmol) of lithiumhydroxide in 10 mL of water. The solution was stirred for two hours atrt. then acidified to pH=1.0 with 5 N HCl and concentrated to dryness togive a quantitative yield of the crude desired product. MS (ion spray)154.1 (M+). Crude product was carried on without further purification.

PREPARATION 304 (Pyridin-4-yloxy)-acetic Acid Ethyl Ester

To a slurry of sodium hydride, 1.73 g (43.2 mmol) in 100 mL of DMF wasadded 3.4 g (36.0 mmol) of 4-hydroxypyridine. The mixture was stirred 10minutes then added to a solution of 3.3 mL (30.0 mmol) ofbromoethylacetate in 100 mL DMF. The reaction mixture was stirred 72hours at rt. then concentrated to dryness. The residue was partitionedbetween 20% isopropanol/chloroform and water and washed with saturatedaqueous NaHCO₃, washed with brine, dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by radialchromatography using MeOH/chloroform as eluent and concentrated todryness to yield 510 mg (9.4%) of the desired product as a tan oil.¹H—NMR is consistent with structure. MS (ion spray) 182.1 (M+).

PREPARATION 305 tert-Butylamino-acetic Acid

To a solution of tert-Butylamino-acetic acid methyl ester (Maybridge),122 mg (0.84 mmol) in 10 mL of dioxane was added a solution of 60 mg(2.52 mmol) of lithium hydroxide in 10 mL of water. The reaction mixturewas stirred for two hours, acidified to pH=1 with 5 N HCl andconcentrated to dryness to yield the crude desired product which wascarried on without further purification. MS (IS) 132.1 (M+1).

PREPARATION 306 (6-Methoxy-pyridin-3-ylamino)-acetic Acid

To a solution of (6-methoxy-pyridin-3-ylamino)-acetic acid methyl ester,113 mg (0.58 mmol) in 10 mL of dioxane was added a solution of 70 mg(2.9 mmol) of lithium hydroxide in 10 mL of water. The reaction mixturewas stirred for three hours, acidified to pH=1 with 5 N HCl andconcentrated to dryness to yield the crude desired product which wascarried on without further purification. MS (IS) 183.1 (M+1).

PREPARATION 307 2-(Pyridin-3-yloxy)-propionic Acid

To a solution of 2-(pyridin-3-yloxy)-propionic acid ethyl ester, 320 mg(1.6 mmol) in 10 mL of dioxane was added a solution of 190 mg (8.0 mmol)of lithium hydroxide in 10 mL of water. The reaction mixture was stirredfor three hours, acidified to pH=1 with 5 N HCl and concentrated todryness to yield the crude desired product which was carried on withoutfurther purification. MS (IS) 168.1 (M+1).

PREPARATION 308 1-Benzoyl-pyrrolidine-2-carboxylic Acid Methyl Ester

Benzoyl chloride (1.40 mL, 12.1 mmol) was added in a dropwise manner toa mixture of L-proline methyl ester hydrochloride (2.00 g, 12.1 mmol)and Et₃N (4.20 mL, 30.2 mmol) in CH₂Cl₂ (40 mL) and the resultingmixture stirred overnight at rt. The mixture was concentrated in vacuoand the residue treated with water and extracted with EtOAc and thecombined extracts dried over Na₂SO₄. Concentration left a residue whichwas loaded onto a silica gel column and eluted with MeOH/CH₂Cl₂ whichallowed for isolation of 2.76 g (94%) of the title compound as a whitesolid. MS(ES): (M+1)⁺ 234.2 m/z.

PREPARATION 309 1-Benzoyl-pyrrolidine-2-carboxylic Acid

The compound from preparation 308 (1.00 g, 4.3 mmol) was combined withaqueous 2N sodium hydroxide (4.0 mL, 8.0 mmol), tetrahydrofuran (2.0 mL)and MeOH (2.0 mL) and the mixture stirred at rt. until hydrolysis wascomplete. Organic solvents were removed in vacuo and the mixture wasdiluted with water and adjusted to pH 2.0-3.0 with aqueous hydrochloricacid. The mixture was then concentrated to dryness in vacuo. Theresulting solids were then slurried (and washed) with an EtOAc/ethanolmixture followed by filtration. Concentration of the filtrate leftdesired acid of acceptable purity (0.52 g, 55%) as a white solid.MS(ES): (M+1)⁺ 220.3 m/z.

PREPARATION 310 1-Phenylacetyl-pyrrolidine-2-carboxylic Acid MethylEster

Phenacetyl chloride (1.60 mL, 12.1 mmol) was added to a mixture ofL-proline methyl ester hydrochloride (2.00 g, 12.1 mmol) and Et₃N (4.20mL, 30.2 mmol) in CH₂Cl₂ (40 mL) and the resulting mixture stirredovernight at rt. The mixture was treated in a manner similar to that inpreparation 103, which resulted in recovery of 1.74 g (58%) of thedesired ester as a clear oil. MS(ES): (M+1)⁺ 248.2, 249.2 m/z.

PREPARATION 311 1-Phenylacetyl-pyrrolidine-2-carboxylic Acid

The compound from preparation 310 (1.00 g, 4.0 mmol) was combined withaqueous 2N sodium hydroxide (5.0 mL, 10.0 mmol), tetrahydrofuran (2.0mL) and MeOH (2.0 mL) and the mixture stirred at rt. until hydrolysiswas complete. The mixture was then treated in a manner similar topreparation 104, however when the pH was adjusted the desired acid beganto precipitate. Filtration and drying of the precipitate netted 0.70 g(74%) of the title compound as a white powdery solid. MS(ES): (M+1)⁺234.3.

PREPARATION 312 N-Benzyl-L-proline

N-Benzyl-L-proline ethyl ester (1.00 g, 4.3 mmol) was combined withaqueous 2N sodium hydroxide (5.0 mL, 10.0 mmol), tetrahydrofuran (2.0mL) and MeOH (2.0 mL) and the mixture stirred at rt. until hydrolysiswas complete. The mixture was then treated in a manner similar topreparation 104. Concentration of the filtrate netted 0.79 g (90%) ofcrude acid as a light yellowish solid. MS(ES): (M+1)⁺ 206.3, 207.3.

PREPARATION 3143-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic Acid EthylEster

To a mixture of ethyl3-(2-Fluoro-6-iodo-phenyl)-5-methyl-isoxazole-4-carboxylate (0.25 g,0.67 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.067 mmol),and Et₃N (5 mL) under N₂ was added TMSCN and heated at reflux overnight.The reaction was cooled to room temperature, diluted with H₂O, andextracted with EtOAc (2×). The combined extracts were washed (H₂O thenbrine), dried (MgSO₄), filtered, and concentrated. Flash chromatography(silica gel, EtOAc/hexanes gradient) gave the title compound (0.15 g,82%). Mass Spectrum (ES+) (m/z) 275.0 [M+1].

PREPARATION 3153-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic Acid

A mixture of a compound from preparation 314, (0.14 g, 0.51 mmol), EtOH(2.5 mL), and 5 N NaOH (0.3 mL, 1.5 mmol) was heated at 50° C. for 1.5h. The reaction was cooled to rt., diluted with H₂O, and acidified(conc. HCl) to less than pH 3. The mixture was extracted with EtOAc (2×)and the combined extracts were washed (H₂O then brine), dried (MgSO₄),filtered, and concentrated to give the title compound (0.1 g, 80%). Thismaterial was used without further purification. Mass Spectrum (ES+)(m/z) 247.0 [M+1].

PREPARATION 3163-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylicAcid[3-(benzoylamino-methyl)-cyclohexyl]-amide

To a solution of a compound from preparation 315, (0.1 g, 0.41 mmol) inCH₂Cl₂ (10 mL) under N₂ was added oxalyl chloride (0.07 mL, 0.82 mmol)then DMF (1 drop) and stirred for 2 h. The solution was concentrated,redissolved in CH₂Cl₂ (5 mL) under N₂, andN-(3-amino-cyclohexylmethyl)-benzamide (0.114 g, 0.49 mmol) was added.The reaction vessel was submerged in a water bath and Et₃N (0.17 mL,1.23 mmol) was added dropwise. After 2.5 h of stirring, the mixture wasdiluted with CH₂Cl₂, washed (1.0 NaOH then brine), dried (MgSO₄),filtered, and concentrated. Flash chromatography (silica gel,Acetone/CH₂Cl₂ gradient) gave (0.119 g, 63%). Mass Spectrum (ES+) (m/z)461.2 [M+1].

PREPARATION 317 (3-Amino-cyclohexylmethyl)-carbamic Acid Benzyl Ester

A solution of [3-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamicacid tert-butyl ester (6 g, 16.6 mmol) in TFA (30 mL) was stirred for1.5 h. The solution was concentrated using benzene to azeotrope, dilutedwith EtOAc, washed (1.0 N NaOH), dried (Na₂SO₄), filtered, andconcentrated to afford (4.2 g, 97%) as a crude solid. Mass Spectrum(ES+) (m/z) 263.1 [M+1].

PREPARATION 318(3-{[3-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-cyclohexylmethyl)-carbamicAcid Benzyl Ester

In a fashion similar to that described for preparation 316, a compoundfrom preparation 315 (3.05 g, 12.4 mmol), oxalyl chloride (2.16 mL, 24.8mmol), CH₂Cl₂ (50 mL), DMF (0.05 mL),(3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (4.2 g, 16.1mmol), CH₂Cl₂ (125 mL), and Et₃N (5.17 mL, 37.2 mmol) gave the titlecompound (4.6 g, 76%) after flash chromatography (silica gel,acetone/CH₂Cl₂ gradient). Mass Spectrum (ES+) (m/z) 491.2 [M+1].

PREPARATION 319 2-(3-Oxo-cyclohexyl)-malonic Acid Dibenzyl Ester

To a solution of LiAlH₄ (6 mL, 6 mmol) under N₂ at 0° C. was added asolution of (S)-1,1′-binaphthol (3.43 g, 12 mmol) in THF (48 mL) andstirred for 30 min. The reaction was warmed to RT. To this was added asolution of sodium salt benzyl malonate in THF which was prepared byreacting benzyl malonate (14.99 mL, 60 mmol), NaH (60% by wt., 0.216 g,5.4 mmol), and THF (60 mL) until all bubbling ceased. Next,cyclohexenone (5.82 mL, 60 mmol) and dibenzlmalonate (1.35 mL, 5.4 mmol)were added and the reaction mixture was stirred overnight. 1.0 N HCl wasadded and extracted with EtOAc (3×). The combined EtOAc layers werewashed (brine), dried (MgSO₄), filtered, and concentrated. Flashchromatography (silica gel, acetone/hexanes gradient) gave the titlecompound (16.17 g, 71%). Mass Spectrum (FIA) (m/z) 381.3 [M+1].

PREPARATION 320 2-(3-Hydroxy-cyclohexyl)-malonic Acid Dibenzyl Ester

To a −78° C. solution of a compound from preparation 319 (see Arai, T.;Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasali, M. Chem. Eur. J.1996, 2, 1368-1372.) (16.15 g, 42.5 mmol) in THF (212.5 mL) under N₂ wasadded L-selectride (46.75 mL at 1.0 M, 46.75 mmol) dropwise and themixture was stirred for 3.5 h at −78° C. EtOAc and H₂O were added andthe mixture was warmed to rt. Dilution with more EtOAc followed bywashing with 1N NaOH, saturated NH₄Cl, brine, drying (MgSO₄), and flashchromatography (silica gel, EtOAc/hexanes gradient) gave the titlecompound (14.29 g, 88%). Mass Spectrum (FIA) (m/z) 383.3 [M+1].

PREPARATION 321 (3-Hydroxy-cyclohexyl)-acetic Acid Benzyl Ester

A solution of a compound from preparation 320 (19.19 g, 50.2 mmol, LiCl(4.27 g, 100.5 mmol, H₂O (1.81 mL, 100.5 mmol), and DMSO (135 mL) waslowered into a 165° C. oil bath for 2 h then heated at 175° C. for 1.5h. The reaction was cooled to rt. and diluted with EtOAc. Washing withH₂O and brine, drying (MgSO₄), and flash chromatography (silica gel,EtOAc/hexanes gradient) gave the title compound (9.71 g, 78%). 1H NMR:consistent with structure.

PREPARATION 322 (3-Azido-cyclohexyl)-acetic Acid Benzyl Ester

To a solution of a compound from preparation 321 (9.71 g, 39.2 mmol),Ph₃P (12.32 g, 41.04 mmol), and hydrazoic acid (30.9 mL, at 1.9 M, 58.7mmol) in toluene (120 mL) was added DEAD (9.24 mL, 58.7 mmol) dropwiseand stirred for 72 h. The mixture was diluted with EtOAc, washed with0.1 N NaOH, H₂O, and brine, dried (MgSO₄), and chromatographed (silicagel, CH₂Cl₂/hexanes gradient) to give the title compound (10.0 g, 93%).1H NMR: consistent with structure.

PREPARATION 323 (3-tert-Butoxycarbonylamino-cyclohexyl)-acetic AcidBenzyl Ester

A mixture of a compound from preparation 322 (10 g, 36.6 mmol), (BOC)₂O(9.57 g, 43.9 mmol), Lindlar's catalyst (3.7 g), and EtOAc (200 mL) wasstirred under an atmosphere of hydrogen gas (balloon) for 24 h, filteredthrough celite, and concentrated. Flash chromatography (silica gel,EtOAc/hexanes gradient) gave the title compound (7.03 g, 55%). MassSpectrum (FD+) (m/z) 347.3 [M⁺].

PREPARATION 324 (3-tert-Butoxycarbonylamino-cyclohexyl)-acetic Acid

In a fashion similar to that described for preparation 315, a compoundfrom preparation 323 (7 g, 20.2 mmol), 2 N NaOH (25 mL, 50 mmol),Dioxane (100 mL) were reacted for 5 h to give the title compound (5.2 g,100%). Mass Spectrum (FD+) (m/z) 257.3 [M⁺].

PREPARATION 325 [3-(Benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamicAcid tert-butyl Ester

To a solution of a compound from preparation 324 (2.6 g, 10.1 mmol),Et₃N (2.84 mL, 20.4 mmol) in toluene (100 mL) under N₂ was added DPPA(4.39 mL, 20.4 mmol) and benzyl alcohol (3.13 mL, 30.3 mmol). Thesolution was heated to reflux overnight. The reaction was cooled to roomtemperature, diluted with EtOAc, washed (1.0 N NaOH then brine), dried(MgSO₄), filtered, and concentrated. Flash chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (2.92 g, 80%). 1H NMR:consistent with structure.

PREPARATION 326 (3-Aminomethyl-cyclohexyl)-carbamic Acid tert-butylEster

A mixture of a compound from preparation 325 (1 g, 2.76 mmol), 10% Pd/Ccatalyst (0.5 g), and EtOAc (30 mL) was stirred under an atmosphere ofhydrogen gas (balloon) for 18 h, filtered through celite, andconcentrated to give (0.48 g, 76%) which was taken on without furtherpurification. Mass Spectrum (S+) (m/z) 229.1 [M+1].

PREPARATION 327[3-({[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-methyl)-cyclohexyl]-carbamicAcid tert-butyl Ester

To a solution of a compound from preparation 326 (0.48 g, 2.1 mmol) and3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (0.75g, 2.74 mmol) in CH₂Cl₂ (20 mL) under N₂ was added dropwise Et3N (0.73mL, 5.25 mmol) and stirred for 4 h. The reaction was diluted withCH₂Cl₂, washed (H₂O then brine), dried (MgSO₄), filtered, andconcentrated. Flash chromatography (silica gel, hexanes/EtOAc gradient)gave the title compound (0.726 g, 74%). Mass Spectrum (ES+) (m/z) 366.1[M−BOC].

PREPARATION 3285-Chloro-3-(2-chloro-6-fluoro-phenyl)-isoxazole-4-carboxylicacid[3-(benzoylamino-methyl)cyclohexyl]amide

In a fashion similar to that described for preparation 316, (0.22 g,0.84 mmol), CH₂Cl₂ (2 mL), oxalyl chloride (0.15 mL, 1.68 mmol), DMF(0.01 mL), CH₂Cl₂ (5 mL), N-(3-Amino-cyclohexylmethyl)-benzamide (0.15g, 0.65 mmol), and Et₃N (0.35 mL, 2.52 mmol) gave the title compound(0.29 g, 90%) after flash chromatography (silica gel, Acetone/CH₂Cl₂gradient). Mass Spectrum (ES+) (m/z) 490.1 [M+1].

PREPARATION 3293-(2-Chloro-6-fluoro-phenyl)-5-diethylamino-isoxazole-4-carboxylicAcid{3-[(2-propenyl-penta-2,-dienoylamino)-methyl]-cyclohexyl}-amide

To a solution of a compound from preparation 328 (0.1 g, 0.2 mmol) inDMF (2.5 mL) under N₂ was added diethylamine (0.065 mL, 0.63 mmol) andstirred for 2 h. The reaction was diluted with EtOAc, washed (H₂O thenbrine), dried (MgSO₄), filtered, and concentrated. (0.1 N HCl andbrine), dried (MgSO4), filtered, and concentrated. Flash chromatography(silica gel, acetone/CH₂Cl₂ gradient) gave the title compound (0.1 g,93%). Mass Spectrum (ES+) (m/z) 527.2 [M+1].

PREPARATION 3303-(2-Chloro-6-fluoro-phenyl)-5-pyrrolidin-1-yl-isoxazole-4-carboxylicAcid[3-(benzoylaminomethyl)-cyclohexyl]-amide

In a fashion similar to that described for preparation 329, a compoundfrom preparation 328 (0.085 g, 0.17 mmol), DMF (2.5 mL), pyrrolidine(0.14 mL, 1.7 mmol) gave (0.089 g, 100%) which was taken on as a cruderesidue. Mass Spectrum (ES+) (m/z) 525.2 [M+1].

PREPARATION 3313-(2-Chloro-6-fluoro-phenyl)-5-ethylamino-isoxazole-4-carboxylicacid[3-(benzoylaminomethyl)-cyclohexyl]-amide

In a fashion similar to that described for preparation 329, a compoundfrom preparation 328 (0.085 g, 0.17 mmol), DMF (2.5 mL), ethylamine(0.85 mL, 1.7 mmol) gave the title compound (0.085 g, 100%) which wastaken on as a crude residue. Mass Spectrum (ES+) (m/z) 499.2 [M+1].

PREPARATION 3323-(2-Chloro-6-fluoro-phenyl)-5-ethylsulfanyl-isoxazole-4-carboxylicacid[3-(benzoylamino-methyl)-cyclohexyl]-amide

In a fashion similar to that described for preparation 329, a compoundfrom preparation 328 (0.1 g, 0.2 mmol), DMF (2.5 mL), sodiumethanethiolate (0.103 g, 1.0 mmol) gave the title compound (0.85 g,100%) which was taken on as a crude residue. ¹H NMR: consistent withstructure.

PREPARATION 333[3-({[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-methyl)-cyclohexyl]-carbamicAcid tert-butyl Ester

A mixture of a compound from preparation 326 (0.85 g, 2.35 mmol), 10%Pd/C catalyst (0.5 g), and EtOAc (25 mL) was stirred under an atmosphereof hydrogen gas (balloon) for 18 h, filtered through celite, andconcentrated. This residue was mixed with3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (0.772g, 2.82 mmol) in CH₂Cl₂ (7 mL) under N₂ and to this solution was addeddropwise Et₃N (1.0 mL, 7.05 mmol). After stirring 48 h, the mixture wasdiluted with CH₂Cl₂, washed (0.1 N HCl then brine), dried (MgSO₄),filtered, and concentrated. Flash chromatography (silica gel,EtOAc/Hexanes gradient) gave the title compound (0.64 g, 58%). MassSpectrum (ES+) (m/z) 366.3 [M−BOC].

PREPARATION 3345-[3-(Benzoylamino-methyl)-cyclohexyl]-3-methyl-4-oxo-4,5-dihydro-isoxazolo[4,3-c]quinolin-9-yl}-carbamicAcid 2-trimethylsilanyl-ethyl Ester

To a solution of3-methyl-4-oxo-5-{3-[(phenylcarbonylamino)methyl]-cyclohexyl}-5-hydroisoxazolo[4,3-c]quinoline-9-carboxylicacid (0.25 g, 0.55 mmol), Et₃N (0.118 mL, 0.845 mmol) in toluene (3.5mL) under N₂ was added DPPA (0.18 mL, 0.845 mmol) and 2-(trimethylsilyl)ethanol (0.232 mL, 1.63 mmol). The solution was heated to reflux for 4h. The reaction was cooled to rt., diluted with EtOAc, washed (1.0 NNaOH then brine), dried (MgSO₄), filtered, and concentrated. Columnchromatography (silica gel, acetone/CH₂Cl₂ gradient) gave the titlecompound (0.285 g, 90%). Mass Spectrum (ES−) (m/z) 573.3 [M−1]

PREPARATION 335[3-(3,4,5-Trimethoxy-phenylcarbamoyl)-cyclopentylmethyl]-carbamic Acidtert-butyl Ester

To a solution of 0.224 g (0.92 mmols) of3-[(t-butoxy)amino]cyclopentane-carboxylic acid was added 0.44 mmol of1-hydroxy-7-azabenzotriazole and 0.44 mmol of EDCI. After 40 minutes,0.44 mmol of 3,4,5-trimethoxyaniline was added. After 3.25 hours, thesolvent was removed in vacuo and replaced with ethyl acetate. Theorganic layer was rinsed with 1 N HCl, aq. NaHCO₃, and then ×3 withwater. The organic layer was dried and the solvent was removed in vacuoto yield 0.34 g of the title compound.

MS(ES+)m/z=409.

PREPARATION 336 3-Aminomethyl-cyclopentanecarboxylic Acid(3,4,5-trimethoxy-phenyl)-amide

A solution of 0.049 g (0.12 mmol) of a compound from preparation 335 inTFA (10 ml) was stirred for 1 hour, after which the TFA was removed invacuo and replaced with ethyl acetate. The organic layer was rinsed with1N NaOH followed by brine and dried. The organic layer was removed invacuo to yield 0.013 g of the title compound.

MS(ES+)m/z=308.

PREPARATION 3373-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole4-carboxylicAcid[3-(3,4,5-trimethoxy-phenylcarbamoyl)-cyclopentylmethyl]-amide

A solution of 0.013 g (0.042 mmol) of a compound from preparation 336,0.03 g (0.46 mmol) of3-(6-chloro-2-fluorophenyl)-5-methylisoxazole4-carbonyl chloride, and0.07 ml (0.5 mmol) of triethylamine in dichloromethane (10 ml) wasstirred for 12 hours. The solvent was removed in vacuo and replaced withethyl acetate. The organic layer was washed with 1N HCl, then aq.NaHCO3, followed by brine and dried. The solvent was removed in vacuothen chromatographed on silica gel with CH₂Cl₂ 100% to CH₂Cl₂/MeOH 2% toyield 0.018 g of the title compound. MS(ES+)m/z=545.8.

PREPARATION 338(3-{[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-cycloheptyl)-aceticAcid Methyl Ester

A solution of 4.4 g (24 mmol) of methyl 2-(3-aminocycloheptyl)acetate,0.03 g (0.46 mmol) of3-(6-chloro-2-fluorophenyl)-5-methylisoxazole4-carbonyl chloride, and0.07 ml (0.5 mmol) of triethylamine in dichloromethane (10 ml) wasstirred for 12 hours. The solvent was removed in vacuo and replaced withethyl acetate. The organic layer was washed with 1N HCl, then aq.NaHCO3, followed by brine and dried. The solvent was removed in vacuothen chromatographed on silica gel with hexane/EtOAc 3/1 to yield 1.7 gof the title compound. MS(ES+)m/z=423.

PREPARATION 3395-(3-Aminomethyl-cycloheptyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

To a solution of 0.43 g (1.02 mmol) ofN-{[3-(9-chloro-3-methyl-4-oxo(5-hydroisoxazolo[4,3-c]quinolin-5-yl))cycloheptyl]methyl}methoxycarboxamidein CH₂Cl₂ (10 mL) was added 0.35 mL of trimethylsilyl iodide(2.1 mmol)and the solution was stirred for 15 hours at ambient temperature. MeOH(1.5 mL) was added and the reaction was stirred for 15 min. before thesolvent was removed in vacuo. The residue was dissolved in CH₂Cl₂ andrinsed with 1N NaOH followed by 50% brine/water. After drying overNa₂SO₄, the solvent was removed to yield 0.397 g of the title compound

MS(ES+)m/z=360.1.

PREPARATION 340 tert-butylamino-pyridin-3-yl-acetic Acid Ethyl Ester

A typical synthesis of bromo-pyridin-3-yl-acetic acid ethyl ester isdescribed: A solution of fresh lithium diisopropylamide (IDA) wasprepared at −10° C. from diisopropylamine (8.54 mL; 60.5 mmol) andn-butyllithium (nBuLi) (37.8 mL of a 1.6 M hexanes solution; 12.1 mmol)and stirred for 10 min. After chilling the fresh LDA to −78° C., ethyl3-pyridylacetate (9.21 mL; 60.5 mmol) was added and the solution wasstirred another 10 min. TMSCl (7.68 mL; 60.5 mmol) was added to theresulting opaque yellow slurry and the solution was stirred 5 min.Finally a solution of 4-(dimethylamino) pyridinium tribromide (22.0 g;60.5 mmol) in tetrahydrofuran was added and the reaction solution wasstirred 10 min. After warming to rt. the reaction solution was quenchedwith saturated NH₄CL (aq) and extracted twice with ethyl acetate. Thecombined organic layer was washed once with saturated NaCl (aq), driedwith Na₂SO₄, filtered, and concentrated in vacuo. The resultingbromo-pyridin-3-yl-acetic acid ethyl ester was an unstable brown oil andwas therefore used immediately by preparing aliquots of product indichloromethane and proceeding.

Bromo-pyridin-3-yl-acetic acid ethyl ester (2.4 g; 9.8 mmol) was reactedin refluxing CH₂Cl₂, overnight with tert-butylamine (6.2 mL; 55.8 mmol;6 equiv) and Et₃N (2.8 mL; 19.6 mmol; 2 equiv). The reaction solutionwas evaporated to dryness, dissolved in CH₂Cl₂, washed six times withsaturated NaHCO₃ (aq), washed once with saturated NaCl (aq), dried withNa₂SO₄, filtered, and concentrated in vacuo. The resulting brown oil waspurified with silica gel chromatography in a 6×8 cm glass column using a30% EtOAc/hexanes (v/v) mobile phase. A total of 955 mg desired productwas isolated (41% yield). MS(ES) calc'd: [M+H]+=237.1 m/z. Found: 237.1m/z.

PREPARATION 341 (2,2-dimethyl-propylamino)-pyridin-3-yl-acetic AcidEthyl Ester

Bromopyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol), preparedin a manner similar to preparation 340, was reacted in refluxing CH₂Cl₂,overnight with neopentylamine (4.83 mL; 41.0 mmol; 4 equiv) and Et₃N(5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated todryness, dissolved in CH₂Cl₂, washed five times with saturatedNaHCO₃(aq), washed once with saturated NaCl (aq), dried with Na₂SO₄,filtered, and concentrated in vacuo. The resulting brown oil waspurified with silica gel chromatography in a 3×25 cm glass column usinga 0.5% methanol/chloroform (v/v) mobile phase. A second columnpurification with 100% chloroform followed by 1% methanol/chloroform(v/v) produced pure product as a yellow oil (1.0 g; 40% yield).

MS(ES) calc'd: [M+M]⁺=250.1 m/z. Found: 250.1 m/z.

PREPARATION 342 Dimethylamino-pyridin-3-yl-acetic Acid Ethyl Ester

Bromopyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol) wasreacted in a sealed tube, at rt., in CH₂Cl₂, overnight withN,N-dimethylamine hydrochloride (3.34 g; 41.0 mmol; 4 equiv) and Et₃N(5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated todryness, dissolved in CH₂Cl₂, washed five times with saturated NaHCO₃(aq), washed once with saturated NaCl (aq), dried with Na₂SO4, filtered,and concentrated in vacuo. The resulting brown oil was purified withsilica gel chromatography in a 3×25 cm glass column using a 0.5%methanol/chloroform (v/v) mobile phase. The desired product was isolatedas a yellow oil (1.12 g; 53% yield). MS(ES) calc'd: [M+H]⁺=208.1 m/z.Found: 208.1 m/z.

PREPARATION 343 (4-methyl-piperazin-1-yl)-pyridin-3-yl-acetic Acid EthylEster

Bromo-pyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol), wasreacted in refluxing dichloromethane, overnight with 1-methylpiperazine(4.54 mL; 41.0 mmol; 4 equiv) and Et₃N (5.8 mL; 41.0 mmol; 4 equiv). Thereaction solution was evaporated to dryness, dissolved in CH₂Cl₂, washedfive times with saturated NaHCO₃ (aq), washed once with saturated NaCl(aq), dried with Na₂SO₄, filtered, and concentrated in vacuo. Theresulting brown oil was purified with silica gel chromatography in a3×17 cm glass column using a 2% methanol/chloroform (v/v) mobile phase.A second column eluted with 30% EtOAc/hexanes (v/v) followed by a stepgradient of 0.5-3% methanol/CH₂Cl₂ (v/v) produced the desired product asa yellow oil (756 mg; 28% yield). MS(ES) calc'd: [M+H]⁺=263.1 m/z.Found: 263.1 m/z.

PREPARATION 344 2-{3-[(t-Butoxy)carbonylamino]cyclohexyl}acetic Acid

A compound from preparation 45 (1.0 g, 2.77 mmol) was dissolved intetrahydrofuran (4 mL) and ethanol (4 mL) under a dry nitrogenatmosphere at room temperature. This cloudy white solution became clearand colorless after mixing with 2N NaOH_((aq)) (15 mL; 19.4 mmol, 11.1equiv) for 2 h. After rotary evaporation to dryness, the white solid wasdissolved in water (20 mL) and the resulting solution extracted withdiethyl ether (twice). Acidification of the aqueous layer to pH 2 with1N HCl_((aq)) produced a white solid that was extracted into ethylacetate (thrice). The EtOAc was washed with saturated NaCl_((aq)), driedwith Na₂SO_(4(s)), and concentrated to dryness by rotary evaporation.The resulting white solid (700 mg, 98% yield) was used in subsequentreactions without further purification. MS(ES) calc'd: [M+Na]⁺=280.2m/z, [M−H]⁻=256.2 m/z. Found: 280.1 m/z; 256.2 m/z.

PREPARATION 345N-((1S,3R)-3-{[(phenylmethoxy)carbonylamino]methyl}cyclohexyl)(t-butoxy)carboxamide

To a solution of a compound from preparation 344 (3.43 g, 13.35 mmol),Et₃N (3.75 mL, 26.96 mmol) in toluene (86 mL) under N₂ was added DPPA(5.8 mL, 26.96 mmol) and benzyl alcohol (4.28 mL, 41.38 mmol). Thesolution was heated to reflux overnight. The reaction was cooled to rt.,diluted with EtOAc, washed (1.0N NaOH then brine), dried (MgSO₄),filtered, and concentrated. Column chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (3.05 g, 63%). MassSpectrum (ES+) (m/z) 263.1 [M−BOC].

PREPARATION 346N-(cis-3(S)-Aminocyclohexylmethyl)(phenylmethoxy)carboxamide

A compound from preparation 345 (1.0 g, 2.76 mmol) was treated with TFA(5 mL) under N₂. After 20 min of stirring at rt. the reaction wascomplete. The crude was then concentrated to an oil which was purifiedon a Varian Bond-Elut SCX column (10 g). The column was elutedconsecutively with CHCl₃, MeOH, and ammonia (2.0M in MeOH). The pureproduct was recovered from the ammonia fractions. The solvent wasremoved in vacuo to afford 0.632 g (87%) as a colorless oil. MS (ES+)m/z 263.0 (M+H)⁺.

PREPARATION 347(3-{[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4carbonyl]-amino}-cyclohexylmethyl)-carbamicAcid Benzyl Ester

To a mechanically stirred solution of crude compound from preparation346 (20.1 g, 76.6 mmol) and TEA (46.9 g, 459.4 mmol) in 185 ml ofdichloromethane was added a compound from preparation 344 (23.1 g, 84.2mmol) in one portion. The solution warmed slightly and a precipitatebegan to form. The reaction mixture was stirred at ambient temperaturefor 19 hours. TLC analysis (20% EtOAc/dichloromethane) showed completeconsumption of the starting material. The reaction mixture was dilutedwith 200 ml of dichloromethane and washed sequentially with 2×200 ml of1N hydrochloric acid, 2×200 ml of saturated aqueous sodium bicarbonatesolution, and 200 ml of half-saturated aqueous NaCl solution. Thesolution was dried over magnesium sulfate and concentrated to a paleyellow oil, which solidified upon standing. The solid was trituratedwith 150 ml of diethyl ether, stirred for one hour, filtered, washedwith a small amount of diethyl ether, and dried in vacuo at 25° C. toprovide 29.3 g (76%) of the title compound as a white solid. ¹H NMR (300MHz, CDCl₃) 7.48 (m, 1H), 7.35 (m, 6H), 7.17 (dt, J=8.5 Hz, 0.9 Hz, 1H),5.08 (s, 2H), 4.98 (d, J=7.9 Hz, 1H), 4.72 (m, 1H), 3.73 (m, 1H), 3.01(m, 2H), 2.76 (s, 3H), 1.90 (m, 1H), 1.67 (m, 3H), 1.52 (m, 1H), 1.28(m, 1H), 0.69 (m, 2H), 0.43 (q, J=12.0 Hz, 1H).

PREPARATION 348[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-carbamicAcid Benzyl Ester

To a mechanically stirred solution of compound from preparation 347(27.6 g, 55.2 mmol) in 450 ml of DMF was added a 0.5M solution ofpotassium bis(trimethyl-silyl)amide in toluene (133 ml, 66.3 mmol) over15 minutes. The resulting purple solution was stirred at ambienttemperature for 5 minutes at which time TLC analysis (20%EtOAc/dichloromethane) indicated that all of the starting material hadbeen consumed. The reaction was diluted with 1 L of EtOAc and quenchedwith 500 ml of water. The two layers were stirred together for 15minutes and separated. The aqueous layer was extracted twice with 250 mlof EtOAc and the combined organic layers were washed twice with 500 mlof water and once with 500 ml of half-saturated NaCl solution. Thesolution was dried over magnesium sulfate and concentrated to an orangesolid. The solid was slurried in a minimal amount of EtOAc, filtered,washed with a small amount of ethyl acetate, and dried in vacuo toafford 17.9 g of the title compound as an off-white solid. An additional4.4 grams of the title compound were isolated by flash chromatography ofthe filtrate. Total yield was 22.3 g (84%). ¹H NMR (300 MHz, CDCl₃) 7.40(m, 2H), 7.33 (m, 6H), 5.06 (s, 2H), 4.85 (m, 1H), 3.16 (m, 2H), 2.89(s, 3H), 2.56 (br m, 1H), 2.37 (br m, 1H), 1.98 (m, 1H), 1.81 (m, 5H),1.46 (m, 1H), 1.07 (m, 1H).

PREPARATION 3495-(3-Aminomethyl-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-oneHydroiodide

To a 0° C. solution of compound from preparation 348 (5.0 g, 10.4 mmol)in dichloromethane (100 mL) was added iodotrimethylsilane (3.6 mL, 25.0mmol) dropwise, and the solution allowed to warm to room temperatureovernight. Methanol (6.1 mL, 150.0 mmol) was added dropwise over twominutes, and the reaction stirred for 30 minutes. The reaction wasconcentrated and suspended in ethyl ether. After 15 minutes ofsonication, the solids were removed by filtration and washed with ethylether. The tan powder was dried on a vacuum pump to give 4.61 g of thetitle compound as the 1.2 HI salt, 89% yield. MS (ion spray) 346 (M⁺).

PREPARATION 350 (t-Butoxy)-N-[(3-nitrophenyl)methyl]carboxamide

To a suspension of 5.00 g (26.5 mmol) of 3-nitrobenzylaminehydrochloride in 100 mL CH₂Cl₂ at rt. was added 5.79 g (26.5 mmol) ofdi-t-butyl dicarbonate. To this was added 8.13 mL (58.3 mmol) oftriethylamine, dropwise over 15 min. The reaction was stirred for 3 h atrt., after which it was diluted with 300 mL of EtOAc. The resultingorganic solution was washed three times with 1N HCl solution, dried oversodium sulfate and concentrated in vacuo to give 6.2 g (93%) of a whitesolid, which was characterized as the title compound. MS (FIA) m/z=253.

PREPARATION 351 (t-Butoxy)-N-[(3-aminocyclohexyl)methyl]carboxamide

To a solution containing 12.0 g (47.7 mmol) of a compound frompreparation 350 in 300 mL ethanol was added 6.0 g of rhodium on carbon.The reaction was subjected to hydrogenation (60 psi) at 60° C. for 18 h,after with the catalyst was removed by vacuum filtration and the solventremoved in vacuo, giving 9.5 g (87%) of a clear oil. This material wascharacterized as the title compound and used without furtherpurification. ¹H—NMR is consistent with structure.

PREPARATION 352N-(3{[t-Butoxy)carbonylamino]methyl}cyclohexyl)[4-(2-chloro-6-fluorophenyl)-2-methyl(3-furyl)]carboxamide

To a solution of 9.5 g (41.6 mmol) of a compound from preparation 351 in200 mL of CH₂Cl₂ was added 11.4 g (41.6 mmol) of a compound frompreparation 344, followed by 11.6 mL (83.2 mmol) of TEA at rt. Thereaction was stirred at room temperature for 15 h, and concentrated invacuo. The crude solid was dissolved in 200 mL of ethyl acetate and theorganic solution was washed twice with 1N HCl solution, dried oversodium sulfate and concentrated in vacuo to give a yellow solid. Thismaterial was recrystallized from methanol to give 12.5 g (64%) of awhite crystalline solid, which was characterized as the title compound,as an inseparable mixture of cis and trans isomers. MS(FIA) m/z=466.2.

PREPARATION 353(t-Butoxy)-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}carboxamide

To a stirred solution of 7.00 g (15.0 mmol) of a compound frompreparation 352 in 200 mL of DMF at rt. was added 30.0 mL (15 mmol) of a0.5 M toluene solution of potassium bis(trimethylsilyl) amide over 10min. The resulting dark red reaction was stirred an additional 5 min atrt. and added to 200 mL of 1N HCl. The two phase solution was dilutedwith 400 mL of ethyl acetate and the organic layer was separated. Theorganic solution was washed four times with brine, dried over sodiumsulfate and concentrated in vacuo to give an orange solid. This materialwas recrystallized from toluene to give 3.4 g of a light yellow solid,which was characterized as pure racemic cis material, (a). MS(FIA)m/z=446.1. Purification of the racemic trans material (b) wasaccomplished by concentrating the mother liquor and subjecting thismaterial to flash chromatography on silica gel, using 50% hexane-EtOAcas the eluent. The major fractions were combined to give a light yellowsolid, which was characterized as pure racemic trans material. MS(FIA)m/z=446.1.

PREPARATION 354N-{3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}(t-butoxy)carboxamide

The racemic material of a compound from preparation 353 was separatedinto its enantiomers by chiral HPLC chromatography using a Chiralpak ADcolumn and 10% ethyl alcohol-heptane as the eluent at a flow of 1.0mL/min.

Retention Time (Enantiomer 1)=10.501 min.

Retention Time (Enantiomer 2)=12.576 min.

PREPARATION 355N-[3-(aminomethyl)cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

A slurry of a compound from 354 (1.2 g, 2.7 mmol) in 20 mL of aceticacid saturated with hydrochloric acid was stirred for 4 h at rt., thenconcentrated to dryness. The residue was dissolved in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes,concentrated to dryness, and dried under vacuum to yield 750 mg (80%) ofthe desired mixture of isomers as a tan solid. MS (ion spray) 346.2(M+1).

PREPARATION 357 1-Methyl-piperidine-3-carboxylic Acid

To a solution of ethyl 1-methylnipecotate, 0.3 mL (1.65 mmol) in 10 mLof dioxane was added a solution of 118 mg (4.95 mmol) of lithiumhydroxide in 10 mL of water. The solution was stirred for 1.5 hours atrt. then was acidified to pH=1 with 5N HCl. The mixture was concentratedto dryness and carried on without further purification. IS (MS) 144.1(M+1).

PREPARATION 358 Piperidine-1,3-dicarboxylic Acid 1-tert-butyl Ester

To a solution of nipecotic acid, 2.0 g (16.0 mmol) in 20 mL of THF and20 mL of water was added 4.7 g (33.6 mmol) of potassium carbonate and3.5 g (16.0 mmol) of Boc-anhydride. The resulting solution was stirredovernight at ambient temperature then concentrated to dryness. Theresidue was dissolved in water, washed with ether and acidified to pH=2with 5N HCl. The acidic aqueous layer was extracted with 20%isopropanol/chloroform. The combined organics were washed with brine,dried over sodium sulfate, filtered and concentrated to dryness to yield3.2 g (86%) of the desired mixture of isomers as a white solid. MS (ionspray) 228.2 (M−1).

PREPARATION 359{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamyl]-methyl}-carbamicAcid tert-butyl Ester

To a solution of a compound from preparation 69, 130 mg (0.28 mmol) in10 mL of DMF was added 59 mg (0.34 mmol) of N-t-butoxycarbonylglycine,46 mg (0.34 mmol) of 1-hydroxy-7-azabenzo-triazole, 66 mg (0.34 mmol) ofEDC, 5 mg of DMAP and 0.120 mL (0.84 mmol) of Et₃N. The reaction mixturewas stirred overnight at rt. and was concentrated to dryness. Theresidue was dissolved in 20% isopropanol/chloroform, washed withsaturated NaHCO₃, washed with brine, dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by radialchromatography using a MeOH/chloroform gradient and concentrated todryness. The residue was slurried in ether/hexanes and concentrated todryness to yield 97 mg (71%) of the desired isomer as a white foam. MS(ion spray) 489.1 (M+).

PREPARATION 3602-Amino-N-[3-(9-chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-acetamideHydrochloride

A solution of the compound from preparation 359, 49 mg (0.10 mmol) in 10mL of HCl-saturated acetic acid was stirred 3 hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to give a quantitative yield of the desiredisomer as a tan foam. MS (ion spray) 389.1 (M+).

PREPARATION 361 2-(Pyridin-3-yloxy)-hexanoic Acid Ethyl Ester

To a solution of ethyl-3-bromohexanoate, 5.0 g (22.4 mmol) in 200 mL oftetrahydrofuran was added 4.6 g (26.9 mmol) of 3-hydroxypyridine sodiumsalt. The mixture was refluxed for four hours and concentrated todryness. The residue was partitioned between 20% isopropanol/chloroformand water. The organics were washed with saturated aqueous sodiumbicarbonate, washed with brine, dried over sodium sulfate, filtered, andconcentrated to dryness. The residue was purified by columnchromatography using a methanol/chloroform gradient as eluent andconcentrated to dryness to yield 1.82 g (34%) of the desired mixture ofisomers as a brown liquid. MS (ion spray) 238.2 (M+1).

PREPARATION 362 2-(Pyridin-3-yloxy)-hexanoic Acid

A solution of lithium hydroxide, 200 mg (8.82 mmol) in 10 mL of waterwas added to a solution of compound from the preparation 361, 700 mg(2.94 mmol) in 10 mL of dioxane. The resulting solution was stirred atambient temperature for 3 hours, acidified to pH=1 with 5 N HCl andconcentrated to dryness. Crude MS (ion spray) 210.0 (M+1) for desiredmix of isomers. Crude product was carried on as is without furtherpurification.

PREPARATION 363 (Pyrimidin-2-yloxy)-acetic Acid Ethyl Ester

To a slurry of sodium hydride (60% dispersion in mineral oil), 280 mg(5.76 mmol) in 10 mL of DMF at 0° C. was added 0.52 mL (4.8 mmol) ofethyl glycolate. After 10 minutes, 0.92 g (5.76 mmol) of2-bromopyrimidine was added. The reaction mixture was stirred 15 min at0° C. then ice bath was removed. After four hours, reaction mixture wasquenched with methanol and concentrated to dryness. The residue waspartitioned between 20% isopropanol/chloroform and water, then extractedwith 20% isopropanol/chloroform. The combined organics were washed withsaturated aqueous sodium bicarbonate, washed with brine, dried oversodium sulfate, filtered, and concentrated to dryness. The residue waspurified by radial chromatography using a methanol/chloroform gradientas eluent and concentrated to dryness to yield 0.45 g (52%) of thedesired product as a colorless oil. MS (ion spray) 183.1 (M+1).

PREPARATION 364 (Pyrimidin-2-yloxy)-acetic Acid

A solution of lithium hydroxide, 260 mg (11.0 mmol) in 5 mL of water wasadded to a solution of 400 mg (2.2 mmol) of compound from preparation363 in 5 mL of dioxane. The mixture was stirred for four hours atambient temperature, then was acidified to pH=1 with 5 N HCl andconcentrated to dryness. The residue was carried on without furtherpurification. MS (ion spray) 155.1 (M+l).

PREPARATION 3653-Methyl-5-(2-chloro-6-fluorophenyl)4-isoxazolecarboxylic Acid EthylEster

To a solution of ethyl 3-aminomethyl crotonate (4.79 g, 33.5 mmol) intoluene (10 mL), was added triethylamine (3.73 g, 37 mmol). The solutionwas chilled using an ice bath, and then 2-chloro-6-fluorobenzoylchloride (6.47 g, 33.5 mmol) was added dropwise over a 20 min period.The reaction was allowed to warm slowly to r.t., and stirred for 24 hr.The resulting suspension was then filtered, and the filtrate dilutedwith ethyl acetate (100 mL) and transferred to a separatory funnel. Theorganic layer was sequentially washed with water, brine, dried (sodiumsulfate), and the volatiles removed under reduced pressure to provide2-(2-chloro-6-fluorobenzoyl)-3-methylamino-but-2-enoic acid ethyl ester(9.46 g) as a golden solid, and primarily one geometrical isomer. MS(ES) m/z 299.9 (M+H)⁺.

Crude adduct was then redissolved in glacial HOAc (50 mL) to which wasadded NH₂OH.HCl (1.8 g, 1.1 eq). The solution was then heated to refluxfor 40-45 min to effect isoxazole formation. The reaction mixture wasconcentrated to an oil, diluted with ether, and transferred to a sep.funnel. The organic phase was washed with saturated bicarbonate, brine,then dried. Filtration and concentration afforded crude isoxazole ethylester (7.5 g), which could be used without further purification. MS(+ES) m/z 283.9 (M+H)⁺.

PREPARATION 366 4-Isoxazolecarboxylic Acid, 3-Methyl,5-(2-chloro-6-fluorophenyl)

Hydrolysis of a compound from preparation 365 was accomplished bydissolving the crude ester (7.5 g, approx. 0.027 mol) in THF (250 mL),and adding aq. LiOH (1.344 g in 100 mL, 2 eq) After stirring overnightat r.t., the solution was concentrated to ⅔^(rd) volume, diluted withEtOAc (200 mL) and 50 mL water, transferred to a separatory funnel, andthe aqueous phase collected. The organic phase was washed twice, and thecombined aqueous phase was then acidified with 5N HCl. Back extractionwith three washings of EtOAc was then followed with a brine wash of thecombined organics. After drying over Na₂SO₄, filtration andconcentration, clean isoxazole acid was obtained (2.94 g). MS (−ES) m/z253.8, 255.8 (M−H)⁻.

PREPARATION 3675-(2-Chloro-6-fluoro-phenyl)-3-methyl-isoxazole-4-carbonyl Chloride

To a solution of a compound from preparation 366 (60 mg, 0.234 mmol) inbenzene (4 mL) containing catalytic amount of pyridine (20 μl) was addedoxalyl chloride (23 mL). After heating to reflux for 1 hr, an aliquotwas concentrated under vacuum. 1H—NMR (CDCl₃) 7.53 (d of t, 1H), 7.37(d, 1H), 7.17 (t,1 H). (racemic)

PREPARATION 368 1,3-cyclohexanedicarboxylic Acid

To a suspension of isophthalic acid (500 g, 3 mol) in methanol (2.81)was added 5% Rhodium-on-alumina catalyst (50 g) and acetic acid (150ml). The reaction mixture was shaken under hydrogen (50 psi) at roomtemperature overnight. The mixture was filtered through celite. To thissolution was added fresh 5% Rhodium-on-alumina catalyst (25 g), and themixture was shaken under 50 psi of hydrogen for another 24 hours. Thefinal reaction mixture was filtered through celite. The solution wasconcentrated under vacuum to give 493 g of the title compound as a whitepowder (96.3% yield). m.p. 163-165° C.

PREPARATION 369 3-Oxabicyclo[3.3.1]nonane-2,4-dione

A solution of dicyclohexylcarbodiimide (200 g, 1.16 mol) in CH₂Cl₂ (1000ml) was added dropwise to a suspension of compound from preparation 368(257 g, 1.25 mol) in CH₂Cl₂ (550 ml), and the mixture was stirred atroom temperature for 4 hours. The precipitated dicyclohexylurea wasfiltered and washed several times with cold CH₂Cl₂ (200 ml×3). Thecombined organic layer was concentrated to give a white solid, which wassuspended in MTBE (900 ml). This solid was collected by filtration,washed with MTBE (250 ml), and dried under house vacuum to give thetitle compound (137 g). The filtrate was concentrated to a residue,which was suspended in MTBE (250 ml) to give another 31 g anhydride. Thetotal yield was 168 g (94%). m.p. 138-140° C.

PREPARATION 370 cis-1,3-Cyclohexanedicarboxylic Acid Diethyl Ester

To a solution of compound from preparation 369 (31 g, 0.2 mol) inethanol (anhydrous, 310 ml) was added p-toluenesulfonic acid monohydrate(1.9 g, 10 mmol, 0.05 equiv.) and triethyl orthoformate (50 ml, 0.3mol). The reaction mixture was stirred at 60° C. overnight. Thevolatiles were stripped and the residue was diluted with ethyl acetate(250 ml), washed with water (120 ml) and brine (100 ml), and dried overMgSO₄. After filtration and evaporation, the residue was purified bychromatography. Eluting the column with 10% ethyl acetate in hexaneafforded the title compound (40 g, 87.7% yield).

¹H NMR: (500 MHz, CDCl₃) δ 4.11 (q, J=7.0 Hz, 4H), 2.29 (dt, 2H), 2.11(dd, 1H), 1.97 (m, 211), 1.98 (m, 1 H), 1.53 (q, J=12.5 Hz, 2H),1.30-1.40 (m, 2H), 1.25 (t, J=7.0 Hz, 6H).

PREPARATION 371 1,3-Cyclohexanedicarboxylic Acid, Monoethyl Ester (1R,3S)

To a suspension of compound from preparation 370 (40 g, 17.5 mmol) in pH7.2 phosphate buffer [0.2 M] (1.2 l) was added lipase AY30 (Amano, 16.7g). The mixture was stirred vigorously at room temperature for 30 hours.The mixture was acidified with 10-15% HCl to pH<2, and extracted withethyl acetate (500 ml×2). The combined organic solution was washed withaqueous 10% Na₂CO₃ (100 ml×2) and water (100 ml×2). The combined aqueouslayers were washed again with ethyl acetate (150 ml) and then acidifiedwith 10-15% HCl to pH<2. The acidified aqueous was then extracted withethyl acetate (150 ml×3). The combined organic solution was dried overMgSO₄. After filtration and concentration the title compound (35.6 g,100% yield) was obtained. ¹H NMR (500 MHz, CDCl₃) δ 4.12 (q, J=7.0 Hz,2H), 2.20-2.40 (m, 3H), 1.85-2.05 (m, 3H), 1.5 (q, 2H), 1.35 (m, 2 H),1.24 (t, J=7.0 Hz, 3H), [α]_(D)3.2°, [α]+10.4° (c, 0.434; CHCl₃).[α]_(D)+3.0°, [α]₃₆₅ +9.6° (c, 0.532; CH₃OH).

PREPARATION 372 Ethyl-[3-N-(methylcarbamate)-cyclohexyl]-carboxylate(1R, 3S)

A solution of a compound from preparation 371 (73 g, 365 mmol) intoluene (750 ml) was heated to reflux using a Dean-Stark trap toseparate trace amounts of water. After collecting about 10 ml of water,the mixture was cooled down to about 40-50° C. To this mixture was addedtriethylamine (56 ml, 0.4 mol), and diphenylphosphoryl azide (86.5 ml,0.4 mol). The reaction mixture was stirred at 110° C. for 60 min, cooledto 70° C., and methanol (64 g, 2 mol ) was added with stirring. Afteraddition, the final reaction mixture was then heated to 85° C.overnight. After cooling to room temperature, the mixture was dilutedwith ethyl acetate (700 ml) and washed with water (500 ml). The aqueouslayer was extracted with ethyl acetate (500 ml×2). The combined organicsolution was washed again with water (500 ml) and brine (500 ml). Afterdrying over MgSO₄ and concentration under reduced pressure, the titlecompound was obtained as a colorless oil (86 g, 100%). ¹H NMR: (300 MHz,CDCl₃) δ 4.60 (sb, 1H), 4.13 (q, 2H), 3.65 (s, 3H), 3.50 (sb, 1H), 2.38(t, 1H), 2.23 (d, 1H), 2.00-1.80 (m, 3H) 1.24 (t, 3H), 1.12-0.95 (m,1H).

PREPARATION 373 Ethyl-((1R,3S)-3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl-amino}cyclohexyl)-carboxylate

To a solution of compound from preparation 372 (86 g, 365 mmol) inCH₂Cl₂ (750 ml) was added iodotrimethylsilane (100 g, 500 mmol) in oneportion, at room temperature. The reaction mixture was stirred for 2hours at ambient temperature, cooled to 0-5° C., and methanol (50 ml)was added. After stirring 15 minutes, the solution was concentratedunder reduced pressure. The residue was dissolved in THF (1 l). To thissolution was added water (0.5 l), potassium carbonate (138 g, 1 mol),and a solution of a compound from preparation 27 (110 g, 0.4 mol) in 250ml THF, dropwise. After the addition, the reaction mixture was heated toroom temperature and stirred for 12 hours. THF was removed under housevacuum, water (250 ml) was added, and the mixture was extracted withethyl acetate (500 ml×3). The combined organic solution was washed withsaturated sodium thiosulfate (150 ml), water (500 ml), brine (500 ml)and then dried over MgSO₄. After filtration and evaporation undervacuum, the residue was purified by recrystallization from MTBE (250ml). Repeating this recrystallization procedure three times provided thetitle compound (122.7 g, 82.5% yield) as a white powder. M.S. m/z 409(M⁺, 100%).

PREPARATION 374 Ethyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quindin-5-yl)-cyclohexyl]-carboxylate

To a solution of compound from preparation 373 (78 g, 190 mmol) in DMF(750 ml) was added a solution of KHMDS ([0.5M], 400 ml, 200 mmol). Thetemperature was kept at 25° C. by using an ice-bath. After the additionwas complete, the reaction mixture was analyzed by TLC (silica gel, 50%EtOAc in hexane) and found to be complete. Water (1 l) was added and themixture was extracted with EtOAc (800 ml×3). The combined organicsolution was washed with 1N HCl (250 ml), water (250 ml), brine (250ml), dried over MgSO₄ and concentrated to give a residue which waspurified by recrystallization from MTBE (500 ml) to afford 66 g of thetitle compound as a light yellow powder (89.0% yield). M.S. m/z 389(M⁺+1, 100%).

PREPARATION 375 (1R, 3S)3-(9-chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylCarboxylic Acid

To a solution of compound from preparation 374 (62 g, 160 mmol) in THF(600 ml) was added 5N aqueous sodium hydroxide (120 ml) at roomtemperature. The reaction mixture was heated to 60° C. for 15 hours withstirring. After cooling to room temperature, water (750 ml) was addedand the mixture was washed with ethyl acetate (500 ml). The aqueousphase was separated and acidified with 15% HCl to pH<2. The aqueousphase was then extracted with methylene chloride (1000 ml×3). Thecombined organic extracts were washed again with water (500 ml), brine(500 ml), and dried over MgSO₄. After filtration and evaporation undervacuum, the dark brown residue was suspended in MTBE (1000 ml), andrefrigerated overnight. The mixture was filtered to afford 55.45 g(96.4%) of bright yellow product. M.S. m/e 361 (M⁺, 50%), 225 (100%).

PREPARATION 3762-methyl[(1R,3S)-3-(9-chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]carbamate

To a suspension of compound from preparation 375 (55.4 g, 154 mmol) intoluene (1 l) was added triethylamine (23.7 ml, 170 mmol), anddiphenylphosphoryl azide (36.5 ml, 170 mmol). The reaction mixture wasstirred at 110° C. for 2 hours during which time a solution formed. Thesolution was cooled to 80° C. and methanol (25 g, 0.77 mol) was addedwith stirring. The solution was warmed to 85° C. for 22 hours. Aftercooling to room temperature, the toluene was removed under reducedpressure and the residue was dissolved in dichloromethane (3 l) andwashed with water (1 l). The aqueous phase was extracted withdichloromethane (1 l×2) and the combined organic solution was washedagain with water (500 ml) and brine (500 ml). After drying over MgSO₄,the solution was concentrated under vacuum. The crude product waspurified by crystallization (CH₂Cl₂/MTBE, 0.5 l/2 l) to afford the titlecompound (46.6 g, 78.2%). [α]_(D)+49.2°, [α]₃₆₅+263.3° (c, 0.56; CHCl₃).The filtrate was concentrated to a residue, which was purified bychromatography to obtain a second crop of product (5.1 g). The totalyield was 86.8%. M.S. m/z 476 (M⁺, 25%).

PREPARATION 377[3-(3-Acetyl-4-amino-5-chloro-2-oxo-2H-quinolin-1-yl)-cyclohexyl]-carbamicAcid methyl ester

A compound from preparation 376 (0.1 g, 0.26 mmol) and Mo(CO)₆ (0.13 g,0.51 mmol) were combined in a solution of acetonitrile (5 mL) and water(1 mL). The reaction mixture was heated to reflux while stirring. Afterstirring for 2 hr the reaction was complete. A 10% aqueous EDTA solutionwas added and stirred for an additional 30 minutes. The reaction wasthen transferred to a separatory funnel and washed with water (5×10 mL).The organic solution was filtered through celite and concentrated to adark brown solid under vacuum. The solid was diluted in EtOAc and waspurified by silica gel column chromatography using 50% EtOAc in Hexanesto elute the product. The solvent was removed in vacuo to afford 0.078 gof desired product as a white solid. MS (ES+) m/z 392.2 (M+H)⁺, (ES−)390.2 (M−H)⁻.

PREPARATION 378[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexyl]-carbamicAcid Methyl Ester

A solution of a compound from preparation 377 (0.05 g, 0.13 mmol) inacetic acid (5 mL) was treated with hydroxylamine hydrochloride (13 mg,0.19 mmol). The solution was heated to reflux and stirred 5 hr. Thereaction was then diluted in EtOAc (50 mL) and washed with water (3×10mL), sat'd sodium bicarbonate (3×10 mL), and brine (2×10 mL). Theorganic was dried over sodium sulfate and the solvent removed. The crudeproduct was purified by silica gel column chromatography using 50% EtOAcin Hexanes to elute the product. The solvent was removed in vacuo toafford 0.028 g (56%) of title compound as a white solid. MS (ES+) m/z390.1 (M+H)⁺, (ES−) 388.2 (M−H)⁻.

PREPARATION 3805-(3-Amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

A solution of a compound from preparation 378 (0.38 g, 1.0 mmol) inCH₂Cl₂ (25 mL) was treated with TMSI (0.29 g, 1.5 mmol). The solutionwas stirred for 2 hr at room temperature. The solution was thenconcentrated to a solid and the solid was diluted in EtOAc (100 mL). Theorganic solution was washed with 1.0 N HCl (5×20 mL) and the aqueous wasadjusted to pH˜12 with 5.0 N NaOH. The aqueous was then extracted withCH₂Cl₂ and the solvent was removed to afford 0.26 g (80%) of the titlecompound as a white solid. MS (ES+) m/z 332.1 (M+H)⁺.

PREPARATION 3909-Chloro-3-methyl-5-(3-methylaminomethyl-cyclohexyl)-5H-isoxazolo[4,3-c]quinolin-4-one

To a solution of a compound from the preparation 48 (50 mg, 0.12 mmol)in chloroform (0.6 mL) was added trifluoroacetic acid (0.6 mL) andtriethylsilane (57 μL, 0.35 mmol) dropwise. The solution was stirred atrt. under nitrogen overnight. The solution was concentrated anddissolved in chloroform (1 mL) and aqueous 1N HCl solution (1 mL). Tothis mixture was added dichloromethane (10 mL) and saturated sodiumbicarbonate solution (10 mL). The layers were separated, and the aqueouslayer was extracted with dichloromethane (×3). The combined organiclayers were dried over magnesium sulfate and concentrated to give 13.7mg of the title compound as a brown solid, 32% yield. ¹H NMR: consistentwith structure. MS (ion spray) 360 (M⁺).

PREPARATION 391 Hydroxy-pyridin-2-yl-acetic Acid Methyl Ester

To a dry flask was added 2-pyridine-carboxaldehyde (14.4 mL, 150 mmol)and zinc iodide (5 mg, 0.02 mmol), followed by dropwise addition oftrimethylsilyl cyanide (20.7 mL, 152 mmol) with rapid stirring. Thesolution was stirred under nitrogen at rt. overnight. The solution wastreated with 9N HCl (50 mL, aqueous solution), and stirred undernitrogen at reflux overnight. The solution was partitioned between waterand 20% isopropanol/chloroform, and the aqueous layer concentrated to anorange solid. Methanol was added, the mixture was sonicated, and placedin a 0° C.-freezer overnight. Ammonium chloride was removed byfiltration (×2), and the solution concentrated. The solution was dilutedwith water (500 mL), and basified to pH 8 with aqueous 5N NaOH. Theaqueous layer was extracted with 20% isopropanol/chloroform (×3), andthe organic layers were washed with brine, dried over magnesium sulfateand concentrated to give 14.02 g of yellow solid. The material wassonicated as a suspension in diethyl ether and filtered to removebaseline impurities. Purification by silica gel chromatography (elutingwith 0-1% methanol/chloroform) gave 4.10 g of the title compound as ayellow solid, 16% yield. ¹H NMR: consistent with structure. MS (ionspray) 167 (M⁺).

PREPARATION 392 (tert-Butyl-dimethyl-silanyloxy)-pyridin-2-yl-aceticAcid Methyl Ester

To a solution of a compound from preparation 391 (4.10 g, 24.5 mmol) inDMF (35 mL) was added imidazole (3.34 g, 49.0 mmol) andt-butyldimethylsilyl chloride (7.39 g, 49.0 mmol). The reaction wasstirred at rt. overnight under nitrogen. The reaction was concentratedand dissolved in chloroform, washed with saturated aqueous sodiumbicarbonate solution, brine, dried over magnesium sulfate andconcentrated. Purification by flash chromatography on silica gel(eluting with 10-20% ethyl acetate/hexane) gave 6.07 g of the titlecompound as a clear oil, 88% yield. ¹H NMR: consistent with structure.MS (ion spray) 281 (M⁺).

PREPARATION 393 Hydroxy-pyridin-3-yl-acetic Acid Methyl Ester

To a dry flask in an ice bath was added 3-pyridine-carboxaldehyde (14.5mL, 150 mmol) and zinc iodide (5 mg, 0.02 mmol), followed by dropwiseaddition of trimethylsilyl cyanide (20.7 mL, 152 mmol). The solution wasstirred under nitrogen at rt. overnight. The solution was treated with9N HCl (50 mL, in water), and stirred under nitrogen at refluxovernight. The solution was partitioned between an aqueous 1N HClsolution and chloroform, and the aqueous layer concentrated. Ethanol wasadded, the mixture was heated to 45° C., and ammonium chloride wasremoved by filtration, and the solution concentrated. To a 0° C. flaskwas added methanol (300 mL) followed by dropwise addition of thionylchloride (40 ml, 548 mmol). After ten minutes, the concentrated reactionmixture was added dropwise as a solution in methanol (300 mL), and thereaction was allowed to warm to rt. overnight. The solution wasconcentrated, diluted with water (500 mL), and basified to pH 9 with asaturated aqueous sodium bicarbonate solution. The aqueous solution wasextracted with 20% isopropanol/chloroform (×5), and the organics driedover magnesium sulfate and concentrated to give 18 g of red oil.Purification by silica gel chromatography (eluting with 0-2%methanol/chloroform) gave 11.51 g of the title compound a yellow oil,46% yield. ¹H NMR: consistent with structure. MS (ion spray) 167 (M⁺).

PREPARATION 394 1-tert-Butoxycarbonylamino-cyclopentanecarboxylic Acid

To a suspension of 1-amino-1-cyclopentane carboxylic acid (4.52 g, 35.0mmol) in THF (50 mL) and water (50 mL) was added potassium carbonate(14.51 g, 105.0 mmol), di-t-butyl-dicarbonate (7.72,g, 35.4 mmol), andDMAP (5 mg, 0.04 mmol). The reaction was stirred at rt. under nitrogenovernight. The THF was removed in vacuo, and the remaining aqueoussolution was acidified to pH 5.5 with an aqueous 5N HCl solution. Theaqueous solution was extracted with 20% isopropanol/chloroform (×6),dried over magnesium sulfate, and concentrated to give 1.01 g of thetitle compound as a white solid, 13% yield. ¹H NMR: consistent withstructure. MS (ion spray) 229 (M⁺).

PREPARATION 395 (4-Acetyl-piperazin-1-yl)-pyridin-3-yl-acetic Acid EthylEster

N-acetyl-piperazine (3.7 g; 28.8 mmol; 2.8 equiv) was combined withbromo-pyridin-3-yl-acetic acid ethyl ester (approx. 2.5 g; 10 mmol).Purification on a 3×16 cm silica column using a 30% then 40% ethylacetate/hexanes (v/v) mobile phase followed by a 2%methanol/dichloromethane (v/v) mobile phase resulted in 1.84 g lightyellow oil (approx. 60% yield). MS(ES) calc'd: [M+H]⁺=292.2 m/z;[M+Na]⁺=314.2 m/z.

Found: 292.1 m/z; 314.1 m/z.

PREPARATION 396 Pyridin-3-yl-(pyridin-2-yloxy)-acetic Acid Ethyl Ester

Sodium hydride (520 mg; 21.8 mmol; 1.4 equiv) was stirred with2-hydroxypyridine (1.73 g; 18.2 mmol; 1.2 equiv) in DMF (30 mL) for 15min. This solution was added to an aliquot of bromo-pyridin-3-yl-aceticacid ethyl ester (approx. 3.6 g; 15 mmol) in DMF (20 mL). After stirringovernight, at rt., the resulting opaque black solution was concentratedin vacuo, dissolved in 20% isopropyl alcohol/chloroform, washed 5 timeswith saturated NaHCO_(3(aq)), washed twice with saturated NaCl_((aq)),and dried over Na₂SO_(4(s)). After filtration, the solution wasconcentrated in vacuo and purified by SiO₂ column chromatography on twoconsecutive columns with a 1% methanol/chloroform mobile phase and thenan ethyl acetate/hexanes mobile phase (30%, 40%, 50% step gradient). Alight yellow oil (134 mg; approx. 3% yield) was isolated. MS(ES) calc'd:[M+H]⁺=259.2 m/z. Found: 259.1 m/z.

PREPARATION 397 Pyridin-3-yl-(pyridin-3-yloxy)-acetic Acid Ethyl Ester

The product was prepared in a manner similar to preparation 396 usingthe pre-formed sodium salt of the 3-hydroxypyridine (2.13 g; 18.2 mmol;1.2 equiv) and an aliquot of bromo-pyridin-3-yl-acetic acid ethyl ester(approx. 3.6 g; 15 mmol) in dimethylformamide (20 mL). Columnpurification over SiO₂ (0.5% then 1.5% methanol/chloroform) produced ayellow/orange oil (2.02; approx. 50% yield). MS(ES) calc'd: [M+H]⁺=259.2m/z; [M−H]⁻=257.2 m/z. Found: 259.1 m/z; 257.1 m/z.

PREPARATION 398 Pyridin-3-yl-(pyridin-4-yloxy)-acetic Acid Ethyl Ester

The product was formed in a manner similar to preparation 396 using thein situ-generated sodium salt of the 4-hydroxypyridine (2.13 g; 18.2mmol; 1.2 equiv) and an aliquot of bromo-pyridin-3-yl-acetic acid ethylester (approx. 3.6 g; 15 mmol) in DMF (20 mL). Column chromatographicpurification over SiO₂ (1% methanol/chloroform) produced a yellow/orangeoil (320 mg; approx. 8% yield). MS(ES) calc'd: [M+H]⁺=259.2 m/z. Pound:259.1 m/z.

PREPARATION 3995-(3-Amino-cyclohexyl)-9-chloro-3-methyl-2,5-dihydro-pyrazolo[4,3-c]quinolin4-one

A solution of a compound from preparation 379 (0.150 g, 0.39 mmol) inCH₂Cl₂ (20 mL) was treated with TMSI (0.116 g, 0.58 mmol) and stirred atrt. for 6 hr. The reaction was then treated with MeOH (5 mL) and stirredfor an additional 20 min. The solution was concentrated to an oil andthen ether was added. The solid was filtered to afford 0.095 g (74%) ofthe title compound as an orange solid. MS (ES+) m/z 331.2 (M+H)⁺.

PREPARATION 4003-(2-Chloro-6-fluoro-phenyl)-3-oxo-2-(triphenyl-15-phosphanyidene)-propionicAcid ethyl ester

To a solution of 20.0 g (0.115 mol) of 2-chloro-6-fluorobenzoic acid in150 mL methylene chloride and 0.50 mL of DMF was added 11.0 mL (0.126mol) oxalyl chloride, dropwise at rt. over 15 minutes. The reaction wasstirred at rt. for one hour and concentrated in vacuo. The resultingacid chloride was redissolved in 50 mL of toluene. In a separate flask,34.0 mL (0.138 mol) of bis(trimethylsilyl) acetamide was dissolved in300 mL of toluene. To this was added 40.0 g (0.115 mol) of(carbethoxymethylene)-triphenylphosphorane. The resulting suspension wascooled to 10° C. and stirred as3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4carbonyl chloride in 50mL of toluene was added dropwise. The cold bath was removed and thereaction was allowed to stir at rt. for 18 hours. The mixture wasconcentrated in vacuo and to the resulting solid was added 50 mL oftoluene. The white solid was collected by vacuum filtration to give 49.0g (84%) of the title compound. MS(ES+) (m/z) 505.1 [M+1].

PREPARATION 401 3-(2-Chloro-6-fluoro-phenyl)-2,3-dioxo-propionic AcidEthyl Ester

A solution of 25.0 g (49.5 mmol) of the compound from preparation 400 in125 mL of methylene chloride was cooled to −78° C. Into the cooledsolution was passed ozone, prepared using an ozone generator (GriffinTech. Corp.) and oxygen at 1.8 amps. The ozone was bubbled through thecooled solution using a gas dispersion tube. The reaction was monitoredvisually, and determined to be completed after 45 minutes, due to thecharacteristic blue color that is associated with an ozone saturatedsolution of methylene chloride. The reaction was purged with nitrogengas and warmed to rt. The organic solution was washed twice with brine,dried over sodium sulfate and concentrated in vacuo. This crude materialwas purified by flash chromatography (silica gel, 50% hexanes-ethylacetate) to give 13.0 g (98%) of the title compound as a yellow oil.Anal. Calcd. for C₁₁H₈O₄FCl: C, 51.08; H, 3.12. Found: C, 50.67; H,3.12.

PREPARATION 402 5-(2-Chloro-6-fluoro-phenyl)-3H-imidazole-4-carboxylicAcid Ethyl Ester

A solution containing 6.80 g (26.0 mmol) of a compound from preparation401 in 50 mL of glacial acetic acid was added to a slurry of 20.3 g (260mmol) of ammonium acetate in 100 mL of glacial acetic acid. To thismixture was added 3.95 g (130 mmol) of paraformalehyde. The mixture wasstirred and heated at 80° C. for one hour and concentrated in vacuo. Theresulting crude material was taken up in ethyl acetate and washed withsaturated sodium bicarbonate (3×). The organic solution was dried oversodium sulfate and concentrated in vacuo to give an oily yellow solid.This crude material was precipitated out of 50% ethyl acetate-hexane togive 3.35 g (48%) of the title compound as a light yellow amorphoussolid. MS (ES+) (m/z) 269.0 [M+1].

PREPARATION 403 & 4045-(2-Chloro-6-fluorophenyl)-3-methyl-3H-imidazole-4-carboxylic AcidEthyl Ester (isomer 1)5-(2-Chloro-6-fluorophenyl)-1-methyl-1H-imidazole-4-carboxylic acidethyl ester (isomer 2)

To a solution containing 2.90 g (10.8 mmol) of the compound frompreparation 402 in 15 mL of DMF was added 2.98 g (21.6 mmol) of solidanhydrous potassium carbonate, followed by 1.34 mL (21.6 mmol) of methyliodide, with stirring, at rt. The reaction was stirred at rt. for onehour, diluted with 100 mL of ethyl acetate and washed four times withbrine. The resulting crude material was purified by flash chromatography(silica gel, hexanes-ethyl acetate gradient) and two main products wereseparated. The major product contained 1.62 g (53%) and was identifiedas the title compound (isomer 1). The isomeric minor product, which wasidentified as the title compound (isomer 2) was found to contain 933 mg(31%).

isomer 1: Mass spectrum (ES+) (m/z) 283.0 [M+1].

Anal. Calcd. for C₁₃H₁₂N₂O₂FCl: C, 55.23; H, 4.28; N, 9.91. Found: C,55.14; H, 4.26; N, 9.75.

isomer 2: Mass spectrum (ES+) (m/z) 283.0 [M+1].

Anal. Calcd. for C₁₃H₁₂N₂O₂FCl: C, 55.23; H, 4.28; N, 9.91. Found: C,55.08; H, 3.96; N, 9.77.

PREPARATION 4055-(2-Chloro-6-fluoro-phenyl)-3-methyl-3H-imidazole-4-carboxylic Acid

To a solution of 95 mg (0.336 mmol) of a compound from preparation 403.in 5 mL methanol was added 5 mL of 1N sodium hydroxide solution. Thereaction was stirred at rt. for 18 hours. The pH of the reaction wasadjusted to pH˜1 with 1N HCl and this material was concentrated in vacuoby adding 100 mL of toluene to aid in the azeotropic removal of water.The subsequent white solid, which contained the free acid. The crudetitle compound was used without further purification.

General Procedures, Unless Otherwise Specified

a) For Condensation of a Primary Amine with a Carboxylic Acid

To “Starting Material A,” the primary amine of interest (1 eq.), inanhydrous DMF at 0° C. was added “Starting Material B,” the carboxylicacid (3 eq.), collidine (3 eq.) and BOP (3 eq.). The cold bath wasremoved and after 2 h. The reaction was diluted with EtOAc (25 mL) andsaturated NaHCO₃ (25 mL). The organic layer was washed with distilledH₂O (2×25 mL), dried over Na₂SO₄, and chromatographed on silica gel.

b) For Acylation of Primary Amines

To a solution of “Starting Material A,” the primary amine (1 eq.), indichloromethane was added “Starting Material B,” the acylating reagent(1 eq.), triethylamine (1 eq.), and 4-dimethylaminopyridine (10%mol.eq.). The mixture was stirred overnight at ambient temperature andchloroform was added. The solution was washed with 1N hydrochloric acid,saturated sodium bicarbonate, then brine; dried over sodium sulfate,filtered, and the solvent was removed in vacuo. The residue waschromatographed on silica gel to afford the desired compound.

c) For Coupling of Primary Amines and Carboxylic Acids, using1-(3-(dimethylamino)-propyl)3-ethylcarbodiimide HCl (EDC)

To a solution of “Starting Material A,” the carboxylic acid (1 eq.), inN,N-dimethylformamide was added “Starting Material B,” the primary amine(1 eq.), along with EDC (1 eq.), 1-hydroxy-7-azabenzotriazole (1 eq.),4-dimethylaminopyridine (10% mol. eq.), and triethylamine (1 eq.). Themixture was stirred overnight at ambient temperature and concentrated todryness. The residue was partitioned between 20% isopropanol/chloroformand 1N hydrochloric acid. The mixture was washed with 1N hydrochloricacid, saturated sodium bicarbonate, brine, dried over sodium sulfate,filtered and concentrated to dryness. The residue was chromatographed onsilica gel.

d) For Cyclization of2-((1R,3S)-3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cycloalkylCompounds using Potassium t-butoxide (KOtBu)

A solution of “Starting Material” (1 eq.) and 1 eq. of 1.0 N (in THF)KOtBu in DMF was stirred for 3 hours. The reaction was diluted withethyl acetate and washed 5 times with water; dried and concentrated invacuo to a residue, which was chromatographed on silica gel.

e) For Cyclization of2-(3-}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol4yl]-carbonylamino}cycloalklyCompounds using potassium bis(trimethylsilyl)amide (KHMDS)

A solution of “Starting Material” (1 eq.) dissolved in dry DMF wasstirred and cooled to 0° C. in an ice bath. The reaction was thentreated with KHMDS (1.5 eq., 0.5M in THF) and was allowed to warm toroom temperature. After 30 minutes the reaction was diluted in EtOAc,transferred to a separatory funnel, and washed consecutively with 1NHCl, saturated sodium bicarbonate, brine and dried over sodium sulfate.The solvent was removed in vacuo and the residue was chromatographed onsilica gel to afford the desired compound.

f) For Arylation of a Primary Amine

To a stirred solution of “Starting Material A,” the primary amine (1eq.), in DMF was added K₂CO₃ (2 eq.) and “Starting Material B,” thearylhalide (3 eq.). The reaction mixture was stirred at 50° C. for 8hours. It was diluted with ethyl acetate, washed (brine), dried(Na₂SO₄), filtered and concentrated. Column chromatography on silica gelfor purification was preformed.

g) Enantiomeric Separation of the 1R,3S and 1S,3R isomer Configurationof the cycloalkl Examples

The racemic material was separated into its enantiomers by chiral HPLC,using a Chiralpak AD column and 30% isopropyl alcohol-heptane as theeluent at a flow of 1.0 mL/min.

Ex. Starting Starting # Product Material A Material B Physical DataComments a) Table for condensation using collidine: 1cis-1-(9-chloro-3-methyl-4-oxo- prep 69 phenylacetic ESIMS m/e 450 ³⁵Cl(M⁺ + 1) 5H-isoxazolo[4,3-c]quinolin-5- acid and 452 ³⁷Cl (M⁺ + 1)yl)-3-[(phenylmethylcarbonyl)- amino]cyclohexane 2cis-1-(9-chloro-3-methyl-4-oxo- prep 69 3-methoxy- ESIMS m/e 480 ³⁵Cl(M⁺ + 1) 5H-isoxazolo[4,3-c]quinolin-5- phenylacetic and 482 ³⁷Cl(M⁺ + 1) yl)-3-[(3-methoxyphenyl)- acid methyl]carbonyl]amino]-cyclohexane 3 cis-1-(9-chloro-3-methyl-4-oxo- prep 692-(4-fluorophenyl)- ESIMS m/e 468 ³⁵Cl (M⁺ + 1)5H-isoxazolo[4,3-c]quinolin-5- acetic acid and 470 ³⁷Cl (M⁺ + 1)yl)-3-[(4-fluorophenyl)- methyl]carbonyl]amino]- cyclohexane 4cis-1-(9-chloro-3-methyl-4-oxo- prep 69 2-(4- ESIMS m/e 480 ³⁵Cl(M⁺ + 1) 5H-isoxazolo[4,3-c]quinolin-5- methoxyphenyl)- and 482 ³⁷Cl(M⁺ + 1) yl)-3-[(4-methoxyphenyl)methyl]- acetic acidcarbonyl]amino]cyclohexane 5 cis-1-(9-chloro-3-methyl-4-oxo- prep 692-(2- ESIMS m/e 480 ³⁵Cl (M⁺ + 1) 5H-isoxazolo[4,3-c]quinolin-5-methoxyphenyl)- and 482 ³⁷Cl (M⁺ + 1) yl)-3-[(2-methoxyphenyl)methyl]-acetic acid carbonyl]amino]cyclohexane 6 cis-1-(9-chloro-3-methyl-4-oxo-prep 69 2-(2-fluorophenyl)- ESIMS m/e 468 ³⁵Cl (M⁺ + 1)5H-isoxazolo[4,3-c]quinolin-5- acetic acid and 470 ³⁷Cl (M⁺ + 1)yl)-3-[(2-fluorophenyl)methyl]- carbonyl]amino]cyclohexane 7cis-1-(9-chloro-3-methyl-4-oxo- prep 69 2-(3-fluorophenyl)- ESIMS m/e502 ³⁵Cl (M + ³⁵Cl⁻) 5H-isoxazolo[4,3-c]quinolin-5- acetic acid and 504³⁷Cl (M+ ³⁵Cl⁻) yl)-3-[(3-fluorophenyl)methyl]-carbonyl]amino]cyclohexane 8 cis-1-(9-chloro-3-methyl-4-oxo- prep 692-(2-pyridyl)acetic ESIMS m/e 451 ³⁵Cl (M⁺ + 1)5H-isoxazolo[4,3-c]quinolin-5- acid and 453 ³⁷Cl (M⁺ + 1)yl)-3-[(pyrid-2-yl)methyl]- carbonyl]amino]cyclohexane 9cis-1-(9-chloro-3-methyl-4-oxo- prep 69 2-(3-pyridyl)acetic ESIMS m/e451 ³⁵Cl (M⁺ + 1) 5H-isoxazolo[4,3-c]quinolin-5- acid and 453 ³⁷Cl(M⁺ + 1) yl)-3-[(pyrid-3-yl)methyl]- carbonyl]amino]cyclohexane 10(1S,3R)-1-(9-chloro-3-methyl-4-oxo- prep 68 (2S)-2-[(t-butoxy)- ESIMSm/e 565 ³⁵Cl (M⁺ + 1) 5H-isoxazolo[4,3-c]- carbonylamino]-2- and 567³⁷Cl (M⁺ + 1) quinolin-5-yl)-3-{[(2S)- phenylacetic acid2-[[(1,1-dimethylethyloxy)- carbonyl]-amino]-2- (phenyl)acetyl]amino}-cyclohexane 11 (1R,3S)-1-(9-chloro-3-methyl-4-oxo- prep 69(2R)-2-[(t-butoxy)- ESIMS m/e 565 ³⁵Cl (M⁺ + 1) 5H-isoxazolo[4,3-c]-carbonylamino]-2- and 567 ³⁷Cl (M⁺ + 1) quinolin-5-yl)-3-[[(2R)-2-[[-phenylacetic acid (1,1-dimethylethyloxy)carbonyl]-amino]-2-(phenyl)acetyl]amino]- cyclohexane 12(1R,3S)-1-(9-chloro-3-methyl-4-oxo- prep 69 (2S)-2-[(t-butoxy)- ESIMSm/e 565 ³⁵Cl (M⁺ + 1) 5H-isoxazolo[4,3-c]- carbonylamino]-2- and 567³⁷Cl (M⁺ + 1) quinolin-5-yl)-3-[[(2S)- phenylacetic acid2-[[(1,1-dimethylethyloxy)- carbonyl]-amino]-2- (phenyl)acetyl]amino]-cyclohexane 13 (1S,3R)-1-(9-chloro-3-methyl-4-oxo- prep 68(2R)-2-[(t-butoxy)- ESIMS m/e 565 ³⁵Cl (M⁺ + 1) 5H-isoxazolo[4,3-c]-carbonylamino]-2- and 567 ³⁷Cl (M⁺ + 1) quinolin-5-yl)-3-[[(2R)-phenylacetic acid 2-[[(1,1-dimethylethyloxy)- carbonyl]-amino]-2-(phenyl)acetyl]amino]- cyclohexane b) Table for Acylation: 14N-{[(1S,3R)-3-(9-chloro- prep 44 cyclohexylcar- MS (ion spray)3-methyl-4-oxo-5H- bonyl chloride 456.2 (M + 1)isoxazolo[4,3-c]quinolin-5- yl))cyclohexyl]methyl}-cyclohexylcarboxamide 15 N-[(1S,3R)-3-(9-chloro-3- prep 44 biphenylcar-MS (ion spray) methyl-4-oxo-5H- bonyl chloride 526.2 (M+)isoxazolo[4,3-c]-quinolin- 5-yl)cyclohexylmethyl](4-phenylphenyl)-carboxamide 16 N-[(1S,3R)-3-(9-Chloro-3-methyl- prep 44acetic MS (ion spray) 4-oxo-5H-isoxazolo[4,3- anhydride 388 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]acetamide 17N-[(1S,3R)-3-(9-Chloro-3-methyl- prep 44 methanesulfon MS (ion spray)4-oxo-5H-isoxazolo[4,3- yl chloride 424.0 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]methanesulfonamide 18N-[(1S,3R)-3-(9-chloro-3-methyl- prep 44 methyl MS (ion spray)4-oxo-5H-isoxazolo[4,3- chloroformate 404.0 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]methoxycarboxamide 19N-[(1R,3S)-3-(methylaminothioxo- prep 44 methyl MS (ion spray)methylamino-methyl)cyclohexyl]- isothiocyanate 419.0 (M + 1)9-chloro-3-methyl-5H-iso- xazolo[4,3-c]quinolin-4-one 20N-[(1S,3R)-3-(9-Chloro-3-methyl- prep 44 isobutyryl MS (ion spray)4-oxo-5H-isoxazolo[4,3- chloride 416.1 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]-2-methylpropanamide 21N-[(1S,3R)-3-(9-Chloro-3-methyl- prep 44 3- MS (ion spray)4-oxo-5H-isoxazolo[4,3- methylthiopro- 448.1 (M + 1)c]quinolin-5-yl)cyclohexyl- pionyl chloride methyl]-3-methylthiopropanamide 22 N-[(1S,3R)-3-(9-chloro-3-methyl- prep 44valeryl chloride MS (ion spray) 4-oxo-5H-isoxazolo[4,3- 430.2 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]pentanamide 23N-[(1S,3R)-3-(9-chloro-3-methyl- prep 44 phenacetyl MS (ion spray)4-oxo-5H-isoxazolo[4,3- chloride 463.9 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]-2-phenylacetamide 24N-[(1S,3R)-3-(9-chloro-3-methyl- prep 44 hydrocinnamoyl MS (ion spray)4-oxo-5H-isoxazolo[4,3- chloride 478.1 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]-3-phenylpropanamide 252-[(1R,3S)-3-(9-Chloro-3-methyl- 3- prep 47 MS (ion spray) prep. 47 was4-oxo-5H-isoxazolo[4,3- arninopyridine 451 (M + 1) converted toc]quinolin-5-yl)cyclohexyl]- the acid N-pyridin-3-ylacetamide chlorideusing oxalyl chloride in DCM 26 2-[(1R,3S)-3-(9-Chloro-3-methyl- 4- prep47 MS (ion spray) prep. 47 was 4-oxo-5H-isoxazolo[4,3- aminopyridine451.2(M + 1) converted to c]quinolin-5-yl)-cyclohexyl]- the acidN-pyridin-4-ylacetamide chloride using oxalyl chloride in DCM 272-[(1R,3S)-3-(9-Chloro-3-methyl- 2- prep 47 MS (ion spray) prep. 47 was4-oxo-5H-isoxazolo[4,3- aminothiazol 457.1 (M + 1) converted toc]quinolin-5-yl)cyclohexyl]- the acid N-thiazol-2-ylacetamide chlorideusing oxalyl chloride in DCM 28 2-[(1R,3S)-3-(9-Chloro-3-methyl-3-aminophenol prep 47 MS (ion spray) prep. 47 was4-oxo-5H-isoxazolo[4,3- 466.2 (M + 1) converted toc]quinolin-5-yl)cyclohexyl]- the acid N-(3-hydroxyphenyl)acetamidechloride using oxalyl chloride in DCM 29N-[(1R,3S)-3-(9-Chloro-3-methyl- prep 48 acetic MS (ion spray)4-oxo-5H-isoxazolo[4,3- anhydride 388 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]acetamide 30N-[(1R,3S)-3-(9-chloro-3-methyl- prep 48 pivaloyl MS (ion spray)4-oxo-5H-isoxazolo[4,3- chloride 430.1 (M + 1) c]-quinolin-5-yl)-cyclohexyl-methyl]-2,2- dimethylpropionamide 31N-[(1R,3S)-3-(9-chloro-3-methyl- prep 48 cyclobutylcar- MS (ion spray)4-oxo-5H-isoxazolo[4,3- bonyl chloride 428 (M + 1) c]quinolin-5-yl)-cyclohexyl-methyl]-cyclobutyl carboxamide 32[(1R,3S)-3-(9-chloro-3-methyl- prep 48 isoxazolecar- MS (ion spray)4-oxo-5H-isoxazolo[4,3- bonyl chloride 441.1 (M + 1) c]-quinolin-5-yl)-cyclohexyl-methyl]-isoxazol-5-yl carboxamide 335-((1S,3R)-3-{[(Methylsulfonyl)- prep 48 methane- MS (ion spray)amino]-methyl}-9-chloro-3- sulfonyl 424.1 (M + 1)methyl-4-oxo-5H-isoxazolo[4,3- chloride c]quinolin-4-one 345-((1S,3R)-3-{[(Phenylsulfonyl)- prep 48 benzenesulfonyl MS (ion spray)amino]-methyl}-9-chloro-3- chloride 486.4 (M + 1)methyl-4-oxo-5H-isoxazolo[4,3- c]quinolin-4-one 35[(1R,3S)-3-(9-Chloro-3-methyl- prep 48 phenyl MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- chloroformate 466.2 (M + 1)quinolin-5-yl)cyclohexyl- methyl]phenoxycarboxamide 36[(1R,3S)-3-(9-Chloro-3-methyl- prep 48 phenyli- MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- socyanate 464.9 (M+)quinolin-5-yl)cyclohexyl- methyl](phenyl-amino)-carboxamide 375-[(1S,3R)-3- prep 48 phenylthioiso- MS (ion spray)(Phenylaminothiomethylamino-methyl) cyanate 48 1.02 (M + 1)cyclohexyl]-9-chloro-3-methyl-4- oxo-5H-isoxazolo[4,3-c]- quinolin-4-one38 [(1R,3S)-3-(9-chloro-3-methyl- prep 48 morpholine MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- carbonyl 459.2 (M + 1)quinolin-5-yl)-cyclohexyl- chloride methyl]morpholin-4-yl carboxamide 39[(1R,3S)-3-(9-chloro-3-methyl- prep 48 cyclohexyl- MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- carbonyl 456.3 (M + 1)quinolin-5-yl)-cyclohexyl- chloride methyl]cyclohexyl carboxamide 40[(1R,3S)-3-(9-chloro-3-methyl- prep 48 picolinoyl MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- chloride HCl 450.9 (M + 1)quinolin-5-yl)cyclohexyl- methyl]pyridin-2-yl carboxamide 41N-[(1R,3S)-3-(9-chloro-3-methyl- prep 48 nicotinoyl MS (ion spray)4-oxo-5H-isoxazolo[4,3- chloride HCl 451.1 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]nicotinamide 42N-[(1R,3S)-3-(9-Chloro-3-methyl- prep 48 isonicotinoyl MS (ion spray)4-oxo-5H-isoxazolo[4,3- chloride HCl 451.1 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]isonicotinamide 43N-[3-(9-Chloro-3-methyl-4-oxo- prep 54 benzoyl MS(FIA) m/z = prep. 54was 5H-isoxazolo[4,3-c]-quinolin- chloride 450 converted to5-yl)cyclohexyl-methyl]benzamide the primary amine using TFA in DCM 44N-[3-(9-Chloro-3-methyl-4-oxo- prep 54 3,4,5-Tri- MS(FIA) m/z = prep. 54was 5H-isoxazolo[4,3-c]-quinolin- methoxybfenzoyl 540.4 converted to5-yl)cyclohexylmethyl]- chloride the primary 3,4,5-trimethoxybenzamideamine using TFA in DCM 45 N-[3-(9-Chloro-3-methyl-4-oxo- prep 544-Methoxy- MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]-quinolin-benzoyl 480.1 converted to 5-yl)cyclohexylmethyl]- chloride the primary4-methoxy-benzamide amine using TFA in DCM 46N-[3-(9-Chloro-3-methyl-4-oxo- prep 54 3-Methoxy MS(FIA) m/z = prep. 54was 5H-isoxazolo[4,3-c]-quinolin- benzoyl 480.2 converted to5-yl)cyclohexylmethyl]- chloride the primary 3-methoxy-benzamide amineusing TFA in DCM 47 N-[3-(9-Chloro-3-methyl-4-oxo- prep 544-Nitrobenzoyl MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]-quinolin-chloride 493.2 converted to 5-yl)cyclohexylmethyl]- the primary4-nitrobenzamide amine using TFA in DCM 48N-[3-(9-Chloro-3-methyl-4-oxo- prep 54 3-Nitrobenzoyl MS(FIA) m/z =prep. 54 was 5H-isoxazolo[4,3-c]-quinolin- chloride 495.1 converted to5-yl)cyclohexyl-methyl]-3- the primary nitrobenzamide amine using TFA inDCM 49 N-[3-(9-Chloro-3-methyl-4-oxo- prep 54 methyl 4- MS(FIA) m/z =prep 54 was 5H-isoxazolo[4,3-c]-quinolin- (chlorocarbon- 508.2 convertedto 5-yl)cyclohexylmethyl]- yl)benzoate the primary4-carbomethoxybenzamide amine using TFA in DCM 50N-[3-(9-Chloro-3-methyl-4-oxo- prep 54 methyl 3- MS(FIA) m/z = prep 54was 5H-isoxazolo[4,3-c]-quinolin- (chlorocarbon- 508.2 converted to5-yl)cyclohexylmethyl]- yl)benzoate the primary 3-carbomethoxybenzamideamine using TFA in DCM 51 N-[3-(9-Chloro-3-methyl-4-oxo- Ex 49 MS(FIA)m/z = prepared by 5H-isoxazolo[4,3-c]-quinolin- 492.2 basic5-yl)cyclohexylmethyl]- hydrolysis 3-carboxybenzamide 52N-[3-(9-Chloro-3-methyl-4-oxo- Ex 50 MS(FIA) m/z = prepared by5H-isoxazolo[4,3-c]-quinolin- 492.2 basic 5-yl)cyclohexylmethyl]-hydrolysis 3-carboxybenzamide 53 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54Benzoyl MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]-quinolin-chloride 450 converted to 5-yl)-R-cyclohexylmethyl]- the primarybenzamide amine using TFA in DCM 54 N-[3S-(9-Chloro-3-methyl-4-oxo- prep54 2-Methoxy- MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin-benzoyl 480.1 converted to 5-yl)-R-cyclohexylmethyl]- chloride theprimary 2-methoxybenzamide amine using TFA in DCM 55N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3-Methoxy- MS(FIA) m/z = prep.54 was 5H-isoxazolo[4,3-c]quinolin- benzoyl 480.2 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 3-methoxybenzamide amineusing TFA in DCM 56 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4-Methoxy-MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin- benzoyl 480.1converted to 5-yl)-R-cyclohexylmethyl]- chloride the primary4-methoxybenzamide amine using TFA in DCM 57N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3-Ethoxy- MS(FIA) m/z = prep. 54was 5H-isoxazolo[4,3-c]quinolin- benzoyl 494.3 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 3-ethoxybenzamide amineusing TFA in DCM 58 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4-Trifluoro-MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]-quinolin- methoxybenzoyl534.2 converted to 5-yl)-R-cyclohexylmethyl]- chloride the primary4-trifluoromethoxybenzamide amine using TFA in DCM 59N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4-Ethoxyben- MS(FIA) m/z = prep.54 was 5H-isoxazolo[4,3-c]quinolin- zoyl chloride 494.3 converted to5-yl)-R-cyclohexylmethyl]- the primary 4-ethoxybenzamide amine using TFAin DCM 60 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3,4-Dimethoxy- MS(FIA)m/z = prep. 54 was 5H-isoxazolo[4,3-c]-quinolin- benzoyl 570.3 convertedto 5-yl)-R-cyclohexylmethyl]- chloride the primary3,4-dimethoxybenzamide amine using TFA in DCM 61N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3,4-methylene- MS(FIA) m/z =prep. 54 was 5H-isoxazolo[4,3-c]-quinolin- dioxybenzoyl 494.2 convertedto 5-yl)-R-cyclohexylmethyl]- chloride the primary3,4-methylenedioxybenzamide amine using TFA in DCM 62N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 2- MS(FIA) m/z = prep. 54 was5H-isoxazolo[4,3-c]quinolin- Fluorobenzoyl 468.2 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 2-fluorobenzamide amineusing TFA in DCM 63 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3- MS(FIA)m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin- Fluorobenzoyl 468.2converted to 5-yl)-R-cyclohexylmethyl]- chloride the primary3-fluorobenzamide amine using TFA in DCM 64N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4- MS(FIA) m/z = prep. 54 was5H-isoxazolo[4,3-c]quinolin- Fluorobenzoyl 468.2 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 4-fluorobenzamide amineusing TFA in DCM 65 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 542,3-Difluoro- MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin-benzoyl 486.4 converted to 5-yl)-R-cyclohexylmethyl]- chloride theprimary 2,3-difluorobenzamide amine using TFA in DCM 66N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 2,4-Difluoro- MS(FIA) m/z =prep. 54 was 5H-isoxazolo[4,3-c]quinolin- benzoyl 486.5 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 2,4-difluorobenzamideamine using TFA in DCM 67 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 542,5-Difluoro- MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin-benzoyl 486.4 converted to 5-yl)-R-cyclohexylmethyl]- chloride theprimary 2,5-difluorobenzamide amine using TFA in DCM 68N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 2,6-Difluoro- MS(FIA) m/z =prep. 54 was 5H-isoxazolo[4,3-c]quinolin- benzoyl 486.6 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 2,6-difluorobenzamideamine using TFA in DCM 69 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 543,4-Difmoro- MS(HA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin-benzoyl 486.4 converted to 5-yl)-R-cyclohexylmethyl]- chloride theprimary 3,4-difluorobenzamide amine using TFA in DCM 70N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3,5-Difluoro- MS(FIA) m/z =prep. 54 was 5H-isoxazolo[4,3-c]quinolin- benzoyl 486.4 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 3,5-difluorobenzamideamine using TFA in DCM 71 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 543,4,5-Trifluoro- MS(ES+) m/z = prep. 54 was5H-isoxazolo[4,3-c]-quinolin- benzoyl 504.1 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 3,4,5-trifluorobenzamideamine using TFA in DCM 72 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 2-MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin- Chlorobenzoyl484.4 converted to 5-yl)-R-cyclohexylmethyl]- chloride the primary2-chlorobenzamide amine using TFA in DCM 73N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3- MS(FIA) m/z = prep. 54 was5H-isoxazolo[4,3-c]quinolin- Chlorobenzoyl 484.4 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 3-chlorobenzamide amineusing TFA in DCM 74 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4-MS(FIA)m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin- Chlorobenzoyl484.4 converted to 5-yl)-R-cyclohexylmethyl]- chloride the primary4-chlorobenzamide amine using TFA in DCM 75N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3- MS(FIA) m/z = prep. 54 was5H-isoxazolo[4,3-c]quinolin- Bromobenzoyl 530.0 converted to5-yl-R-cyclohexylmethyl]- chloride the primary 3-bromobenzamide amineusing TFA in DCM 76 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4- MS(FIA)m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin- Bromobenzoyl 530.0converted to 5-yl)-R-cyclohexylmethyl]- chloride the primary4-bromobenzamide amine using TFA in DCM 77N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4-Iodobenzoyl MS(FIA) m/z =prep. 54 was 5H-isoxazolo[4,3-c]quinolin- chloride 576.1 converted to5-yl)-R-cyclohexylmethyl]- the primary 4-iodobenzamide amine using TFAin DCM 78 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 2- MS(FIA) m/z = prep.54 was 5H-isoxazolo[4,3-c]quinolin- Methylbenzoyl 464.2 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 2-methylbenzamide amineusing TFA in DCM 79 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3- MS(FIA)m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin- Methylbenzoyl 464.2converted to 5-yl)-R-cyclohexylmethyl]- chloride the primary3-methylbenzamide amine using TFA in DCM 80N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4- MS(FIA) m/z = prep. 54 was5H-isoxazolo[4,3-c]quinolin- Methylbenzoyl 464.2 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 4-methylbenzamide amineusing TFAinDCM 81 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3-Trifluoro-MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]-quinolin- methylbenzoyl518.2 converted to 5-yl)-R-cyclohexylmethyl]- chloride the primary3-trifluoromethylbenzamide amine using TFA in DCM 82N-(3S-(9-Chloro-3-methyl-4-oxo- prep 54 4-Trifluoro- MS(FIA) m/z = prep.54 was 5H-isoxazolo[4,3-c]quinolin- methylbenzoyl 518.2 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary4-trifluoromethylbenzamide amine using TFA in DCM 83N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4- MS(ES+) m/z = prep. 54 was5H-isoxazolo[4,3-c]quinolin- phenylbenzoyl 526.0 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 4-phenylbenzamide amineusing TFA in DCM 84 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4-t- MS(HA)m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin- Butylbenzoyl 506.2converted to 5-yl)-R-cyclohexylmethyl]- chloride the primary4-t-butylbenzamide amine using TFA in DCM 85N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 4- MS(ES+) m/z = prep. 54 was5H-isoxazolo[4,3-c]quinolin- Cyanobenzoyl 474.9 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 4-cyanobenzamide amineusing TFA in DCM 86 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 542,6-Dimethyl- MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin-benzoyl 478.2 converted to 5-yl)-R-cyclohexylmethyl]- chloride theprimary 2,6-dimethylbenzamide amine using TFA in DCM 87N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3-Dimethyl- MS(FD) m/z = prep.54 was 5H-isoxazolo[4,3-c]quinolin- amino benzoyl 492.2 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 3-dimethylaminobenzamideamine using TFAinDCM 88 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 544-Dimethyl- MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin-amhiobenzoyl 493.2 converted to 5-yl)-R-cyclohexylmethyl]- chloride theprimary 4-dimethylaminobenzamide amine using TFA in DCM 89N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 naphthalene-1- MS(FIA) m/z =prep. 54 was 5H-isoxazolo[4,3-c]quinolin- carbonyl 500.1 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 1-naphthylcarboxamideamine using TFA in DCM 90 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54naphthalene-2- MS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin-carbonyl 500.1 converted to 5-yl)-R-cyclohexylmethyl]- chloride theprimary 2-naphthylcarboxamide amine using TFA in DCM 91N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 2-Furoyl MS(FIA) m/z = prep. 54was 5H-isoxazolo[4,3-c]quinolin- chloride 440.2 converted to5-yl)-R-cyclohexylmethyl]- the primary 2-furylcarboxamide amine usingTFA in DCM 92 N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 2-ThiopheneMS(FIA) m/z = prep. 54 was 5H-isoxazolo[4,3-c]quinolin- carbonyl 456.3converted to 5-yl)-R-cyclohexylmethyl]- chloride the primary2-thiophenylcarboxamide amine using TFA in DCM 93N-[3S-(9-Chloro-3-methyl-4-oxo- prep 54 3-Thiophene MS(FIA) m/z = prep.54 was 5H-isoxazolo[4,3-c]quinolin- carbonyl 456.3 converted to5-yl)-R-cyclohexylmethyl]- chloride the primary 3-thiophenylcarboxamideamine using TFA in DCM 94 N-[3-(9-Chloro-3-methyl-4-oxo- Ex 567 acetylMS(FIA) m/z = 5H-isoxazolo[4,3-c]quinolin- chloride 507.25-yl)-cyclohexylmethyl]- 3-acetylaminobenzamide 95N-[3-(9-Chloro-3-methyl-4-oxo- Ex 567 methane- MS(FIA) m/z =5H-isoxazolo[4,3-c]-quinolin- sulfonyl 621.4 5-yl)cyclohexylmethyl]-chloride 3-bis-(methanesulfonyl)- aminobenzamide 96N-[3-(9-chloro-3-methyl-4-oxo- prep 64 benzoyl MS (ion spray) prep 64was 5H-isoxazolo[4,3-c]quinolin- chloride 450 (M⁺), 448 converted to5-yl)-2,2-dimethylcyclobutyl- (M⁻ − 1) the amine by methyl]benzamideTBAF in DCM atrt. 97 N-[3-(9-chloro-3-methyl-4-oxo- prep 64 phenylacetylMS (ion spray) prep 64 was 5H-isoxazolo[4,3-c]quinolin- chloride 464(M+), 462 converted to 5-yl)-2,2-dimethylcyclobutyl- (M⁻ − 1) the amineby methyl]-2-phenylacetamide TBAF in DCM atrt. 98N-[3-(9-chloro-3-methyl-4-oxo- prep 64 3,4,5-tri- MS (ion spray) prep 64was 5H-isoxazolo[4,3-c]quinolin- methoxybenzoyl 540 (M⁺), 548 convertedto 5-yl)-2,2-dimethylcyclobutyl- chloride (M⁻ − 1) the amine bymethyl]-3,4,5-trimethoxybenzamide TBAF in DCM atrt. 99N-[3-(9-chloro-3-methyl-4-oxo- prep 68 benzoyl MS (ion spray)5H-isoxazolo[4,3-c]quinolin- chloride 436 (M+)5-yl)cyclohexyl]-benzamide 100 N-[3-(9-chloro-3-methyl-4-oxo- prep 69benzoyl MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- chloride 436 (M+)5-yl)cyclohexyl]-benzamide 101 N-[3-(9-chloro-3-methyl-4-oxo- prep 68phenacetyl MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- chloride 450.1(M + 1) 5-yl)cyclohexyl]-2- phenylacetamide 102N-[3-(9-chloro-3-methyl-4-oxo- prep 69 phenacetyl MS (ion spray)5H-isoxazolo[4,3-c]quinolin- chloride 450.1 (M + 1) 5-yl)cyclohexyl]-2-phenylacetamide 103 Phenyl-carbamic acid 3-(9-chloro- prep 85 phenylMS(ES):(M + 1)⁺ 3-methyl-4-oxo-5H-isoxazolo[4,3- isocyanate 466.2 m/zc]quinolin-5-yl)-cyclohexylmethyl ester 104 N-{2-[3-(9-Chloro-3-methyl-prep 93 trimethylacetyl MS(ES) [M + H]⁺ = 4-oxo-5H-isoxazolo[4,3-c]-chloride 520.2367 m/z quinolin-5-yl)cyclohexyl]- ethyl}-2,2-dimethyl-N-phenylpropionamide 105 9-Chloro-5-{3-[3-chloro-1-oxo- prep 484-chlorobutyryl MS(FIA) (m/z) butyl- chloride 450.1 (M + 1)amino)-methyl]-cyclohexyl}-3- methyl- 5H-isoxazolo[4,3-c]quinolin-4-one106 N-[3-(9-Iodo-3-methyl-4-oxo- Ex 594 benzoyl MS (FIA) (m/z) Ex 594was 5H-isoxazolo[4,3-c]quinoline- chloride 542.3 [M + 1] converted to5-yl)-cyclohexyl-methyl]-benzamide the primary amine using TFA in DCM107 N-[3-(9-chloro-3-methyl-4-oxo- prep 146 phenylsulfonyl MS (ionspray) 5H-isoxazolo[4,3-c]quinolin- chloride 486 QVT), 4845-yl)-cyclohexyl-methyl]- (M⁻ − 1) benzenesulfonamide 108N-[3-(9-chloro-3-methyl-4-oxo- prep 146 nicotinoyl MS (ion spray)5H-isoxazolo[4,3-c]quinolin- chloride HCL 451(M⁺), 4495-yl)-cyclohexyl-methyl]- (M⁻ − 1) nicotinamide 109N-[3-(9-chloro-3-methyl-4-oxo- prep 146 m-anisoyl MS (ion spray)5H-isoxazolo[4,3-c]quinolin- chloride 480 (M⁺), 4785-yl)-cyclohexyl-methyl]-3- (M⁻ − 1) methoxybenzamide 110Pyridine-2-carboxylic acid [3-(9- prep 146 picolinoyl MS (ion spray)chloro-3-methyl-4-oxo-5H- chloride HCL 451 (M⁺), 449isoxazolo[4,3-c]-quinolin- (M⁻ − 1) 5-yl)-cyclohexylmethyl]amide 111N-[3-(9-chloro-3-methyl-4-oxo- prep 146 4- MS (ion spray)5H-isoxazolo[4,3-c]quinolin- fluorobenzoyl 468 (M⁺), 4665-yl)cyclohexyl-methyl]-4- chloride (M⁻ − 1) fluorobenzamide 112N-[3-(9-chloro-3-methyl-4-oxo- prep 146 3- MS (ion spray)5H-isoxazolo[4,3-c]quinolin- fluorobenzoyl 468 (M⁺), 4665-yl)-cyclohexyl-methyl]-3- chloride (M⁻ − 1) fluorobenzamide 113Thiophene-2-carboxylic acid [3-(9- prep 146 2-thiophene- MS (ion spray)chloro-3-methyl-4-oxo-5H- carbonyl 456 (M⁺), 454isoxazolo[4,3-c]-quinolin- chloride (M⁻ − 1) 5-yl)cyclohexylmethyl]amide114 N-[3-(9-chloro-3-methyl-4-oxo- prep 146 isonicotinoyl MS (ion spray)5H-isoxazolo[4,3-c]quinolin- chloride HCL 451 (M⁺), 4495-yl)cyclohexylmethyl]- (M⁻ − 1) isonicotinamide 115N-{[(1R,3R)-3-(9-chloro-3- prep 146 2-furoyl MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3- chloride 440 (M⁺), 438c]quinolin-5-yl))cyclo- (M⁻ − 1) hexyl]methyl}-2- furylcarboxamide 116N-{[(1R,3R)-3-(9-chloro-3- prep 146 phenylacetyl MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3- chloride 440 (M⁺), 438c]quinolin-5-yl))cyclo- (M⁻ − 1) hexyl]-methyl}-2- phenylacetamide 117cis-3-(benzoylamino)-1-(9- prep 146 benzoyl- ESIMS m/e 436chloro-3-methyl-4-oxo-5H- chloride 35Q (M⁺ + 1) &isoxazolo[4,3-c]quinolin- 438 ³7d (M⁺ + 1) 5-yl)cyclohexane 118N-[3-(9-Chloro-3-methyl-4-oxo- Ex 612 benzoyl MS (+ES) m/z5H-isoxazolo[4,5-c]quinolin- chloride 450.0 (M + H)⁺5-yl)cyclohexyl-methyl]benzamide 119 (1S,3R)-N-[3-(9-Chloro-3- Ex 613 4-MS (ES+) m/z methyl-4-oxo-5H-isoxazolo[4,5- fluorobenzoyl 468.0 (M + H)⁺c]quinolin-5-yl)-cyclohexyl- chloride methyl]-4-fluorobenzamide 120(1R,3S)-Thiophene-2-carboxylic Ex 613 2-Thiophene- MS (ES+) m/zacid[3-(9-chloro-3-methyl- carbonyl 456.0 (M + H)⁺4-oxo-5H-isoxazolo[4,5- chloride c]quinolin-5-yl)cyclohexyl-methyl]-amide 121 (1S,3R)-N-[3-(9-Chloro-3- Ex 614 benzoyl MS (ES+) m/zmethyl-4-oxo-5H-isoxazolo[4,5- chloride 450.0 (M + H)⁺c]quinolin-5-yl)cyclohexyl- methyl]benzamide 122(1S,3R)-H-[3-(9-Chloro-3-methyl- Ex 614 4- MS (ES+) m/z4-oxo-5H-isoxazolo[4,5- Fluorobenzoyl 468.0 (M + H)⁺c]quinolin-5-yl)cyclohexyl- chloride methyl]-4- fluorobenzamide 123(1S,3R)-Thiophene-2-carboxylic Ex 614 2-thiophene- MS (ES+) m/z acid[3-(9-chloro-3-methyl- carbonyl 455.9 (M + H)⁺ 4-oxo-5H-isoxazolo[4,5-chloride c]quinolin-5-yl)cyclohexyl- methyl]-amide 124(1S,3R)-N-[3-(9-Chloro-3-methyl- Ex 614 nicotinoyl MS (ES+) m/z4-oxo-5H-isoxazolo[4,5- chloride 451.0 (M + H)⁺c]quinolin-5-yl)cyclohexyl- methyl]nicotinamide 125(1R,3S)-N-[3-(9-Chloro-3-methyl- Ex 615 benzoyl MS (ES+) m/z4-oxo-5H-isoxazolo[4,5- chloride 500.1 (M + H)⁺c]quinolin-5-yl)cyclohexyl- methyl]benzamide 126(1R,3S)-N-[3-(9-Chloro-3-methyl- Ex 615 nicotinyl MS (ES+) m/z4-oxo-5H-isoxazolo[4,5- chloride 451.0 (M + H)⁺c]quinolin-5-yl)-cyclohexyl- methyl]nicotinamide 127N-[3-(9-Chloro-3-methyl- Ex 616 nicotinoyl MS (ES+) m/z4-oxo-5H-isoxazolo[4,5- chloride 451.0 (M + H)⁺c]quinolin-5-yl)cyclohexyl- methyl]nicotinamide 128N-[3-(9-Chloro-3-methyl- Ex 617 nicotinoyl MS (ES+) m/z4-oxo-5H-isoxazolo[4,5- chloride 451.0 (M + H)⁺c]quinolin-5-yl)cyclohexyl- methyl]nicotinainide 129N-[(1S,3R)-3-(9-Chloro- Ex 619 3,4-difluoro- ESMS: 4723-methyl-4-oxo-5H-isoxazolo[4,3- benzoyl (M + 1)⁺c]quinolin-5-yl)cyclopentyl- chloride methyl]-3,4-difluorobenzamide 130N-[(1S,3R)-3-(9-Chloro-3- Ex 620 3-methoxy- ESMS: 466methyl-4-oxo-5H-isoxazolo[4,3- benzoyl (M + 1)⁺c]quinolin-5-yl)cyclopentyl- chloride methyl]-3-methoxybenzamide 131Thiophene-2-carboxylic acid Ex 620 2-thiophene- ESMS: 442(1S,3R)-3-(9-chloro-3-methyl- carbonyl (M + 1)⁺ 4-oxo-5H-isoxazolo[4,3-chloride c]quinolin-5-yl)- cyclopentylmethyl]-amide 132(1S,3R)-3-(2-Chloro-6-fluorophenyl)- Ex 620 2-Chloro-6- ESMS: 5695-methylisoxazole-4-carboxylic fluorobenzoyl (M + 1)⁺ acid[3-(9-chloro-3-methyl-4-oxo- chloride 5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl-methyl]amide 133 Pyrazine-2-carboxylic Ex 620 2-pyrazine-ESMS: 438 acid [(1S,3R)-3-(9-chloro-3- carbonyl (M + 1)⁺methyl-4-oxo-5H-isoxazolo chloride [4,3-c]quinolin-5-yl)-cyclopentylmethyl]-amide 134 N-[(1S,3R)-3-(9-Chloro-3-methyl- Ex 620*(2S)-2-[(t- ESMS: 565 4-oxo-5H-isoxazolo[4,3- butoxy)carbon- (M + 1)+c]quinolin-5-yl)cyclopentyl- ylamino]-2- methyl]-carbamoylphenylmethyl-phenylacetic carbamic acid t-butyl ester acid 1352-Amino-N-[(1S,3R)-3-(9-chloro- Ex 620 (25)-2-araino- ESMS: 4653-methyl-4-oxo-5H-isoxazolo[4,3- 2-phenylacetic (M + 1)+c]quinolin-5-yl)-cyclopentyl- acid methyl]-2-phenylacetamide 136N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo- Ex 620 benzoyl ESMS: 4365H-isoxazolo[4,3-c]quinolin-5- chloride (M + 1)+ylmethyl)cyclopentyl]benzamide 137 N-{(1S,3R)-3-[(9-chloro-3- Ex 6203,4,5-tri- ESMS: 526 methyl-4-oxo-5H-isoxazolo[4,3- methoxybenzoy (M +1)+ c]quinolin-5-yl))- 1 chloride methyl]cyclopentyl}(3,4,5-trimethoxyphenyl)carboxamide 138 N-{(1R,3S)-3-(2-Chloro-6- Ex 6212-chloro-5- ESMS: 570 fluoro-phenyl)-5-methyl- fluoro phenyl (M + 1)+isoxazolo4-carboxylic acid [3- isoxazoyl (9-chloro-3-methyl-4-oxo-5H-chloride isoxazolo[4,3-c]quinolin- 5-ylmethyl)cyclopentyl]amide 139N-{(1R,3S)-3-[(9-chloro-3- Ex 621 3,4,5- ESMS: 526methyl-4-oxo-5H-isoxazolo[4,3- trimethoxy- (M + 1)+c]quinolin-5-yl))methyl] benzoyl cyclopentyl}-(3,4,5- chloridetrimethoxyphenyl)carboxamide 140 N-[(1R,3S)-3-(9-Chloro-3-methyl- Ex 6214- ESMS: 454 4-oxo-5H-isoxazolo[4,3- fluorobenzoyl (M + 1)+c]quinolin-5-ylmethyl)- chloride cyclopentyl]-4-fluorobenzamide 141N-(1R,3S)-3-(9-Chloro-3-methyl- Ex 621 3,4-difluoro- ESMS: 4724-oxo-5H-isoxazolo[4,3- benzoyl (M + 1)+ c]quinolin-5-ylmethyl)-chloride cyclopentyl]-3,4-difluorobenzamide 142N-[(1R,3S)-3-(9-Chloro-3-methyl- Ex 621 pyridine-3- ESMS: 4374-oxo-5H-isoxazolo[4,3- carbonyl (M + 1)+ c]quinolin-5-ylmethyl)-chloride cyclopentyl]nicotinamide 143 N-[(1R,3S)-3-(9-Chloro-3-methyl-Ex 621 3-methoxy- ESMS: 466 4-oxo-5H-isoxazolo[4,3- benzoyl (M + 1)+c]quinolin-5-ylmethyl)- chloride cyclopentyl]-3-methoxybenzamide 144N-{[(1R,3S)-3-(9-Chloro-3- Ex 621 L-N-trifluoro- ESMS: 561methyl-4-oxo-5H-isoxazolo[4,3- acetyl phenyl (M + 1)+c]quinolin-5-ylmethyl)- glycine cyclopentylcarbamoyl]- phenylmethyl}-carbamic acid t-butyl ester 145 1-Acetyl-2,3-dihydro-1H-indole-((2S)indolin- acetic MS (ion spray) 2-carboxylicacid [3-(9-chloro-2-yl)-N- anhydride 519 (M⁺). 3-methyl-4-oxo-5H-isoxazolo[4,3- [(1R,3S)-c]quinolin-5-yl)cyclo- 3-(9-chloro- hexyl]amide 3-methyl-4-oxo-5H-isoxazolo[- 4,3-c]- quinolin-5- yl))cyclo- hexyl]- carboxamide 146N-[3-(9-Chloro-3-methyl-4-oxo- Ex 624 α-toluene- MS (ion spray)5H-isoxazolo[4,3-c]- sulfonyl 486 (M⁺). quinolin-5-yl)-cyclohexyl]-chloride C-phenylmethane sulfonamide 147 (cis){N-[(cis)-3-(9-chloro- Ex470 nicotinoyl MS (ion spray) 3-methyl-4-oxo-5H-isoxazolo[4,3- HCL 571(M⁺). c]quinolin-5-yl))-cyclohexyl]- carbamoyl}phenylmethylpyridine-3-carboxylate 148 (trans){N-[(cis)-3-(9- Ex 471 nicotinoyl MS(ion spray) chloro-3-methyl-4-oxo-5H- HCL 571 (M⁺).isoxazolo[4,3-c]quinolin-5- yl))-cyclohexyl]-carbamoyl}- phenylmethylpyridine-3-carboxylate 149 N-[3-(9-Chloro-3-methyl-4-oxo- Ex 6326-Fluoro- MS m/z 6-Fluoro- 5H-isoxazolo[4,5-c]-quinolin- nicotinic (ES+)nicotinic acid 5-yl)-cyclohexyl-methyl]-6- acid 468.8 was convertedfluoro-nicotinamide (M + H)⁺ to the acid chloride by oxalyl chloride inDCM. 150 6-Chloro-N-[3-(9-chloro-3-methyl- Ex 632 6-Chloro- MS m/z 6-4-oxo-5H-isoxazolo[4,5- nicotinic (ES+) Chloronicotinicc]quinolin-5-yl)cyclohexyl- acid 468.8 acid was methyl]-nicotinamide(M + H)⁺ converted to the acid chloride by oxalyl chloride in DCM. 151N-[3-(9-Chloro-3-methyl-4-oxo- Ex 633 methanesu- MS(ES):5H-isoxazolo[4,3-c]-quinolin- lfonyl (M + 1)⁺ 5-yl)cyclohexyl]-2-chloride 543.0, methanesulfonylamino-2- 545.0 m/z phenylacetamide 152N-[3-(9-Chloro-3-methyl-4-oxo- Ex 251 acetic MS (ion spray)5H-isoxazolo[4,3-c]-quinolin- anhydride 550.2 (M+).5-yl)-cyclohexyl-methyl]-5- diacetylamino-nicotinamide 1536-Acetylamino-N-[3-(9-chloro- Ex 245 acetic MS (ion spray)3-methyl-4-oxo-5H-isoxazolo[4,3- anhydride 508.2 (M+)c]quinolin-5-yl)cyclo- hexylmethyl]-nicotinamide 154N-[3-(9-Chloro-3-methyl-4-oxo- Ex 632 hydrocinn MS (ion spray)5H-isoxazolo[4,3-c]- amoyl 478.1 (M+). quinolin-5-yl)cyclohexyl-chloride methyl]-3-phenylpropionamide 155 [3-(9-Chloro-3-methyl-4-oxo-Ex 634 phenyl MS (ion spray) 5H-isoxazolo[4,3-c]- chloro- 451.96 (M+).quinolin-5-yl)cyclohexyl]- formate carbamic acid phenyl ester 1561-Benzyl-3-[3-(9-chloro-3- Ex 634 benzyl MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3- isocyanate 465.0 (M+)c]quinolin-5-yl)cyclo- hexyl]urea 157 1-[3-(9-Chloro-3-methyl-4-oxo- Ex634 phenyl MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- isothiocya- 467.0(M+) 5-yl)cyclohexyl]-3-phenylthiourea nate 1581-[3-(9-Chloro-3-methyl-4-oxo- Ex 634 phenyl MS (ion spray)5H-isoxazolo[4,3-c]quinolin- isocyanate 451.96 (M+).5-yl)cyclohexyl]-3-phenylurea 159 N-{[3-(9-Chloro-3-methyl-4-oxo- prep243 pivaloyl MS(ES) exact 5H-isoxazolo[4,3-c]quinolin- chloride mass [M]= 5-yl)cyclohexylcarbamoyl]- 548.2190 m/z phenylmethyl}-2,2-dimethylpropionamide 160 N-[3-(9-chloro-3-methyl-4-oxo- Ex 638 methanesuMS(ES) [M + H]⁺ = 5H-isoxazolo[4,3-c]quinolm- Ifonyl 543.1 m/z5-yl)cyclohexyl]-2-methane- chloride sulfonylamino-2-phenyl-acetamide161 Morpholine-4-carboxylic Ex 638 morpholine-4- MS(ES) [M] = acid{[3-(9-chloro-3- carbonyl 577.2092 m/z. methyl-4-oxo-5H-isoxazolo[4,3-chloride c]quinolin-5-yl)- cyclohexylcarbamoyl]- phenylmethyl}amide 162N-{[3-(9-chloro-3-methyl- Ex 640 pivaloyl MS(ES) [M + H]⁺ =4-oxo-5H-isoxazolo[4,3-c]- (isomer 1) chloride 550.2253 m/z.quinolin-5-yl)cyclohexyl- carbamoyl]pyridin-3-ylmethyl}-2,2-dimethylpropionamide (isomer 1) 163 N-{[3-(9-chloro-3-methyl-4-oxo-Ex 640 pivaloyl MS(ES) exact 5H-isoxazolo[4,3-c]quinolin-5- (isomer 2)chloride mass yl)-cyclohexyl-carbamoyl]- [M + H]⁺=pyridin-3-yl-methyl}-2,2- 550.2247 m/z. dimethylpropionamide (isomer 2)164 N-[3-(9-Chloro-3-methyl-4-oxo- Ex 632 6-Fluoro- MS m/z (ES+) 6-5H-isoxazolo[4,5-c]-quinolin- nicotinic 468.8 (M + H)⁺ Fluoronicotinic5-yl)cyclohexylmethyl]- acid acid was 6-fluoronicotinamide converted tothe acid chloride by oxalyl chloride in DCM. 165N-[3-(9-Chloro-3-methyl-4-oxo- Ex 632 5-Fluoro- MS m/z (ES+) 5-Fluoro-5H-isoxazolo[4,5-c]-quinolin- nicotinic 468.8 (M + H)⁺ nicotinic acid5-yl)cyclohexylmethyl]- acid was converted 5-fluoronicotinamide to theacid chloride by oxalyl chloide in DCM. 166N-[3-(9-Chloro-3-methyl-4-oxo- Ex 525 benzoyl MS(ES+) (m/z) Ex 525 was5H-isoxazole-[4,3-c]-quinolin- chloride 450.1 [M + 1] converted to5-ylmethyl)cyclohexyl]benzamide the amine by TFA in DCM. 167N-[3-(9-Chloro-3-methyl-4-oxo- Ex 525 4- MS(ES+) (m/z) Ex 525 was5H-isoxazole-[4,3-c]-quinolin- fluorobenzoyl 468.1 [M + 1] converted to5-ylethyl)cyclohexyl]-4- chloride the amine by fluorobenzamide TFA inDCM. 168 N-[3-(9-Chloro-3-methyl-4-oxo- Ex 525 3,4- MS(ES+) (m/z) Ex 525was 5H-isoxazole-[4,3-c]quinolin- difluoro- 486.1 [M + 1]. converted to5-ylmethyl)cyclohexyl]benzamide benzoyl the amine by chloride TFA inDCM. 169 N-[3-(9-Chloro-3-methyl-4-oxo- Ex 533 benzoyl MS(ES+) (m/z) Ex533 was 5H-isoxazole-[4,3-c]quinolin- chloride 450.1 [M + 1]. convertedto 5-ylmethyl)cyclohexyl]benzamide the amine by TFA in DCM. 170N-[3-(9-Chloro-3-methyl-4-oxo- Ex 533 4- MS(ES+) (m/z) Ex 533 was5H-isoxazole-[4,3-c]-quinolin- fluorobenzoyl 468.1 [M + 1]. converted to5-ylmethyl)-cyclo-hexyl]-4- chloride the amine by fluoro-benzamide TFAin DCM. 171 N-[3-(9-Chloro-3-methyl-4-oxo- Ex 533 3,4- MS(ES+) (m/z) Ex533 was 5H-isoxazole-[4,3-c]-quinolin- difluorobenzoyl 486.1 [M + 1].converted to 5-ylmethyl)cyclohexyl]-3,4- chloride the amine bydifluorobenzamide TFA in DCM. 172 N-[3-(9-Cyano-3-methyl-4-oxo- Ex 532nicotinoyl MS(ES+) (m/z) 5H-isoxazolo[4,3-c]quinolin-5- chloride 442.3[M + 1]. yl)cyclohexyl-methyl]nicotinamide HCL 173N-[3-(9-Chloro-3-methyl-4-oxo- Ex 540 benzoyl MS(ES+) (m/z) Ex 540 was5H-isoxazolo[4,3-c]quinolin-5- chloride 450.3 [M + 1]. converted toylmethyl)cyclohexyl]benzamide the amine by TFA in DCM. 174N-[3-(9-Chloro-3-methyl-4-oxo- Ex 540 4- MS(ES+) (m/z) Ex 540 was5H-isoxazolo[4,3-c]-quinolin- fluorobenzoyl 468.0 [M + 1]. converted to5-ylmethyl)cyclohexyl]-4- chloride the amine by fluorobenzamide TFA inDCM. 175 N-[3-(9-Chloro-3-methyl-4-oxo- Ex 540 3,4- MS(ES+) (m/z) Ex 540was 5H-isoxazolo[4,3-c]quinolin- difluoro- 486.2 [M + 1]. converted to5-ylmethyl)cyclohexyl]-3,4- benzoyl the amine by difluorobenzamidechloride TFA in DCM. 176 N-[3-(9-Chloro-3-methyl-4-oxo- prep 360 mesylMS (ion spray) 5H-isoxazolo[4,3-c]-quinolin- chloride 545.1 (M+)5-yl)cyclohexyl]-bis(2- methanesulfonyl)amino-acetamide 177N-[3-(9-Chloro-3-methyl-4-oxo- prep 380 benzoyl MS (ES+) m/z5H-isoxazolo[4,5-c]-quinolin- chloride 436.1 (M + H)⁺,5-yl)cyclohexyl]-benzamide (ES−) 434.1 (M − H)⁻. 1782-[(1R,3S)-3-(9-Chloro-3-methyl- 3,4-difluoroaniline Prep 47 MS (ES+)m/z = Prep 47 was 4-oxo-5H-isoxazolo[4,3- 485.8 converted toc]quinolin-5-yl)-cyclohexyl]- the acid N-(3,4-difluoro-phenyl)-acetamidechloride by oxalyl chloride in DCM. 179 2-[(1R,3S)-3-(9-Chloro-3-methyl-3,5-difluoroaniline Prep 47 MS (ES+) m/z = Prep 47 was4-oxo-5H-isoxazolo[4,3- 486.1 converted to c]quinolin-5-yl)-cyclo- theacid hexyl]-N-(3,5-difluoro-phenyl)- chloride by acetamide oxalylchloride in DCM. 180 2-[(1R,3S)-3-(9-Chloro-3-methyl- 2-difluoroanilinePrep 47 MS (ES+) m/z = Prep 47 was 4-oxo-5H-isoxazolo[4,3- 468.1converted to the c]quinolin-5-yl)-cyclo- acid chloride byhexyl]-N-(2-fluoro-phenyl)- oxalyl chloride acetamide in DCM. 1812-[(1R,3S)-3-(9-Chloro-3-methyl- benzylamine Prep 47 MS (ES+) m/z = Prep47 was 4-oxo-5H-isoxazolo[4,3- 464.1 converted to thec]quinolin-5-yl)-cyclo- acid chloride by hexyl]-N-Benzyl-acetamideoxalyl chloride in DCM. 182 2-[(1R,3S)-3-(9-Chloro-3-methyl-3,4,5-Trimethoxy- Prep 47 MS (ES+) m/z = Prep 47 was4-oxo-5H-isoxazolo[4,3- benzylarnine 554.2 converted to thec]quinolin-5-yl)-cyclohexyl]- acid chloride byN-(3,4,5-trimethoxy-benzyl)- oxalyl chloride acetamide in DCM. 1832-[(1R,3S)-3-(9-Chloro-3-methyl- 2-Methoxy- Prep 47 MS (ES+) m/z = Prep47 was 4-oxo-5H-isoxazolo[4,3- phenylamine 480.1 converted to thec]quinolin-5-yl)-cyclo- acid chloride by hexyl]-N-(2-methoxy-phenyl)-oxalyl chloride acetamide in DCM. 184 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-Methoxy- Prep 47 MS (ES+) m/z = Prep 47 was 4-oxo-5H-isoxazolo[4,3-phenylamine 480.1 converted to the c]quinolin-5-yl)-cyclo- acid chlorideby hexyl]-N-(4-methoxy-phenyl)- oxalyl chloride acetamide in DCM. 1852-[(1R,3S)-3-(9-Chloro-3-methyl- 2-Methyl- Prep 47 MS (ES+) m/z = Prep47 was 4-oxo-5H-isoxazolo[4,3- phenylamine 464.2 converted to thec]quinolin-5-yl)-cyclo- acid chloride by hexyl]-N-(2-methyl-phenyl)-oxalyl chloride acetamide in DCM. 186 2-[(1R,3S)-3-(9-Chloro-3-methyl-3-Methyl- Prep 47 MS (ES+) m/z = Prep 47 was 4-oxo-5H-isoxazolo[4,3-phenylamine 464.1 converted to c]quinolin-5-yl)-cyclo- the acidhexyl]-N-(3-methyl-phenyl)- chloride by acetamide oxalyl chloride inDCM. 187 2-[(1R,3S)-3-(9-Chloro-3-methyl- 4-Methyl- Prep 47 MS (ES+) m/z= Prep 47 was 4-oxo-5H-isoxazolo[4,3- phenylamine 464.1 converted toc]quinolin-5-yl)-cyclo- the acid hexyl]-N-(4-methyl-phenyl)- chloride byacetamide oxalyl chloride in DCM. 188 2-[(1R,3S)-3-(9-Chloro-3-methyl-2,6-Methyl- Prep 47 MS (ES+) m/z = Prep 47 was 4-oxo-5H-isoxazolo[4,3-phenylamine 478.2 converted to c]quinolin-5-yl)-cyclo- the acidhexyl]-N-(2,6-dimethyl-phenyl)- chloride by acetamide oxalyl chloride inDCM. 189 2-[(1R,3S)-3-(9-Chloro-3-methyl- 4-Amino-benzoic Prep 47 MS(ES+) m/z = Prep 47 was 4-oxo-5H-isoxazolo[4,3- acid methyl ester 508.2converted to c]quinolin-5-yl)-cyclo- the acid hexyl]-N-(4-carbomethoxy-chloride by phenyl)-acetamide oxalyl chloride in DCM. 1902-[(1R,3S)-3-(9-Chloro-3-methyl- 6-Methoxy- Prep 47 MS (ES+) m/z = Prep47 was 4-oxo-5H-isoxazolo[4,3- quinolin-8- 531.0 converted toc]quinolin-5-yl)-cyclo- ylamine the acid hexyl]-N-(6-methoxy-quinoline)-chloride by acetamide oxalyl chloride in DCM. 1912-[(1R,3S)-3-(9-Chloro-3-methyl- Methyl-phenyl- Prep 47 MS (ES+) m/z =Prep 47 was 4-oxo-5H-isoxazolo[4,3- amine 464.0 converted to thec]quinolin-5-yl)-cyclo- acid chloride by hexyl]-N-phenyl-N-methyl-oxalyl chloride acetamide in DCM. 192 2-[(1R,3S)-3-(9-Chloro-3-methyl-Methyl-benzyl- Prep 47 MS (ES+) m/z = Prep 47 was4-oxo-5H-isoxazolo[4,3- amine 478.1 converted to c]quinolin-5-yl)-cyclo-the acid hexyl]-N-benzyl-N-methyl- chloride by acetamide oxalyl chloridein DCM. 193 (3-{[5-(2-Chloro-6-fluoro- Ex 615 prep 405 MS (ES+) (m/z)Prep 405 was phenyl)-3-methyl-3H-imidazole- 499.2 [M + 1] converted tothe 4-carbonyl]-amino}- acid chloride by cyclohexylmethyl)-carbamicoxalyl chloride acid benzyl ester in DCM. 194 N-[3-(9-Chloro-3-methyl-Ex 193 benzoyl MS (ES+) (m/z) Example 193 4-oxo-3,4-dihydro-imidazo[-chloride 449.2 [M + 1] was converted to 4,5-c]quinolin-5-yl)- theprimary cyclohexyl-methyl]- amine by TMSI benzamide in DCM. 1951R,3S-N-[3-(9-Chloro-3-methyl- Ex 621 benzoyl ESMS: 4364-oxo-5H-isoxazolo[4,3- chloride (M + 1)⁺ c] quinolin-5-ylmethyl)-cyclopentyl]-benzamide 196 1R,3S-N-[3-(9-Chloro-3-methyl- Ex 621phenylacetyi- ESMS: 450 4-oxo-5H-isoxazolo[4,3- chloride (M + 1)⁺c]quinolin-5-ylmethyl)- cyclopentyl]-2-phenyl- acetamide 197N-[3-(9-Chloro-3-methyl- prep 399 benzoyl MS (ES+) m/z4-oxo-5H-isoxazolo[4,5- chloride 436.1 (M + H)⁺,c]quinolin-5-yl)-cyclohexyl]- (ES−) 434.1 (M − benzamide H)⁻ 198N-[3-(9-Chloro-3-methyl- prep 390 nicotinoyl MS (ion spray)4-oxo-5H-isoxazolo[4,3- chloride 465 (M⁺) c]quinolin-5-yl)- HCLcyclohexylmethyl]- N-methyl-nicotinamide 199 R(−)Pyridine-2-carboxylicEx 471 picolinoyl MS (ion spray) acid [3-(9-chloro-3-methyl- chloride571 (M⁺) 4-oxo-5H-isoxazolo[4,3- HCL c]quinolin-5-yl)-cyclohexylcarbamoyl]- phenyl-methyl ester 200 R(−)Isonicotinic acid[3-(9- Ex 471 isonicotinoyl MS (ion spray) chloro-3-methyl-4-oxo-chloride HCL 571 (M⁺) 5H-isoxazolo[4,3- c]quinolin-5-yl)-cyclohexylcarbamoyl]- phenyl-methyl ester 201 S(+)Pyridine-2-carboxylicEx 470 picolinoyl MS (ion spray) acid [3-(9-chloro-3-methyl- chloride571 (M⁺) 4-oxo-5H-isoxazolo[4,3- HCL c]quinolin-5-yl)-cyclohexylcarbamoyl]- phenyl-methyl ester 202 S(+)Isonicotinic acid[3-(9- Ex 470 isonicotin MS (ion spray) chloro-3-methyl-4-oxo-5H- oyl571 (M⁺) isoxazolo[4,3-c]-quinolin- chloride 5-yl)-cyclohexylcarbamoyl]-HCL phenyl-methyl ester c) EDC Coupling: 203 9-Chloro-5-(3-{2-[4-(4-prep 39 4-(4-fluoro- MS (ion spray) fluorobenzoyl)-piperidin-1- benzoyl)564.1 (M+) yl]-2-oxo-ethyl}cyclohexyl)- piperidine3-methyl-5H-isoxazolo[4,3- HCL c]quinolin-4-one 2049-Chloro-3-methyl-5-[3-(2- prep 39 Morpholine MS (ion spray)morpholin-4-yl-2-oxoethyl)- 444.2 (M + 1) cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one 205 9-Chloro-3-methyl-5-{3-[2- prep 39 1-phenyl-MS (ion spray) oxo-2-(4-phenylpiperazin-1- piperazine 519.2(M+)yl)oxoethyl]cyclo-hexyl}- 5H-isoxazolo[4,3- c]quinolin-4-one 2065-{3-[2-(4-Acetylpiperazin- prep 39 1-acetyl- MS (ion spray)1-yl)-2-oxoethyl]cyclohexyl}- piperazine 485.3 (M + 1)9-chloro-3-methyl-5H-isoxazolo[- 4,3-c]quinolin-4-one 2072-[3-(9-Chloro-3-methyl-4-oxo- prep 39 cyclopropyl- MS (ion spray)5H-isoxazolo[4,3- amine 414.2 (M + 1) c]quinolin-5-yl)cyclohexyl]-N-cyclopropylacetamide 208 2-[3-(9-Chloro-3-methyl-4-oxo- prep 39cyclobutyl MS (ion spray) 5H-isoxazolo[4,3- amine 428.2 (M + 1)c]quinolin-5-yl)cyclohexyl]- N-cyclobutylacetamide 2092-[3-(9-Chloro-3-methyl-4-oxo- prep 39 Cyclopentyl- MS (ion spray)5H-isoxazolo[4,3- amine 442.2 (M + 1) c]quinolin-5-yl)cyclohexyl]-N-cyclopentylacetamide 210 2-[3-(9-Chloro-3-methyl-4-oxo- prep 39Cyclohexyl MS (ion spray) 5H-isoxazolo[4,3- amine 456.3 (M + 1)c]quinolin-5-yl)cyclohexyl]- N-cyclohexylacetamide 2112-[3-(9-Chloro-3-methyl-4-oxo- prep 39 Cycloheptyl- MS (ion spray)5H-isoxazolo[4,3- amine 470.2 (M + 1) c]quinolin-5-yl)cyclohexyl]-N-cycloheptylacetamide 212 2-[3-(9-Chloro-3-methyl-4-oxo- prep 39N-methyl,N- MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- cyclohexyl-470.02 (M + 1) 5-yl)cyclohexyl]- amine N-cyclohexyl-N-methylacetamide213 2-[3-(9-Chloro-3-methyl-4-oxo- prep 39 2-aminoindane MS (ion spray)5H-isoxazolo[4,3- 490.2 (M + 1) c]quinolin-5-yl)-cyclohexyl]-N-indan-2-yl-acetamide 214 2-[3-(9-Chloro-3-methyl-4-oxo- prep 391-naphthylamine MS (ion spray) 5H-isoxazolo[4,3- 500.2 (M+)c]quinolin-5-yl)cyclohexyl]- N-naphthalen-1-yl-acetamide 2159-Chloro-3-methyl-5-[3-(2- prep 39 Piperidine MS (ion spray)oxo-2-piperidin-1-yl-ethyl)- 442.2 (M + 1) cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one 216 N,N-Dibenzyl-2-[3-(9-chloro- prep 39 DibenzylamineMS (ion spray) 3-methyl-4-oxo-5H- 554.3 (M + 1)isoxazolo[4,3-c]quinolin- 5-yl)-cyclo-hexyl]-acetamide 217N-Benzyl-2-[3-(9-chloro-3- prep 39 N-benzyl,N- MS (ion spray)methyl-4-oxo-5H- (3,4,5-trimethy- 644.3 (M + 1)isoxazolo[4,3-c]-quinolin- oxy- 5-yl)cyclohexyl]-N-(3,4,5- benzyl)aminetrimethoxybenzyl)acetamide 218 2-[3-(9-Chloro-3-methyl- prep 392-aminopyridine MS (ion spray) 4-oxo-5H-isoxazolo[4,3- 451.1 (M + 1)c]quinolin-5-yl)cyclohexyl]- N-pyridin-2-ylacetamide 2192-[3-(9-Chloro-3-methyl-4-oxo- prep 39 3-aminopyridine MS (ion spray)5H-isoxazolo[4,3- 451.1 (M + 1) c]quinolin-5-yl)cyclohexyl]-N-pyridin-3-ylacetamide 220 2-[3-(9-Chloro-3-methyl-4-oxo- prep 394-aminopyridine MS (ion spray) 5H-isoxazolo[4,3- 451.1 (M + 1)c]quinolin-5-yl)cyclohexyl]- N-pyridin-4-ylacetamide 221N-[(1S,3R)-3-(9-Chloro-3- cyclohexane- prep 44 MS (ion spray)methyl-4-oxo-5H- propionic acid 484.2 (M + 1) isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-3- cyclohexylpropanamide 222N-[(1S,3R)-3-(9-chloro-3- 2-pyrazine- prep 44 MS (ion spray)methyl-4-oxo-5H- carboxylic acid 452.1 (M + 1) isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]pyrazin- 2-yl carboxamide 223N-[(1S,3R)-3-(9-Chloro-3- 2-thiophene- prep 44 MS (ion spray)methyl-4-oxo-5H- acetic acid 470.1 (M + 1) isoxazolo(4,3-c]quinolin-5-yl)cyclohexylmethyl]-2- thiophen-2-ylacetamide 224N-[(1S,3R)-3-(9-Chloro- 1-methyl-4- prep 44 MS (ion spray)3-methyl-4-oxo-5H- iraidazoleacetic 468.1 (M + 1) isoxazolo[4,3-c]- acidHCL quinolin-5-yl)cyclo- hexylmethyl]-2-(1-methyl-1H-imidazol-4-yl)-acetamide 225 N-[(1S,3R)-3-(9-Chloro-3- 4-phenoxy-prep 44 MS (ion spray) methyl-4-oxo-5H- benzoic acid 541.8 (M+)isoxazolo[4,3-c]quinolin- 5-yl)cyclohexylmethyl]-4- phenoxy-benzamide226 4-Benzoyl-N-[(1S,3R)-3-(9- 4-benzoyl- prep 44 MS (ion spray)chloro-3-methyl-4-oxo- benzoic acid 554.2 (M+) 5H-isoxazolo[4,3-c]-quinolin-5-yl)-cyclo- hexylmethyl]benzamide 2276-Fluoropyridine-2-carboxylic prep 1 Ex 632 MS (ion spray) acid[3-(9-chloro-3-methyl- 469 (M+) 4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl- methyl]amide 228N-[3-(9-Chloro-3-methyl-4-oxo- D-(−)-mandelic Ex 634 MS (ion spray)flash chrom. 5H-isoxazolo[4,3- acid 484 (M+) (silica gel: 0-c]quinolin-5-yl)cyclohexyl]-2- 0.5% MeOH/(4-fluorophenyl)-2-hydroxyacetamide chloroform) gave both isomers 229Cis-N-{[3-(9-chloro-3-methyl- 4-fluoro- Ex 632 MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- picolinic acid 469 (NT).quinolin-5-yl))cyclo- hexyl]methyl}(5-fluoro(2- pyridyl))-carboxamide230 Cis-N-{[3-(9-chloro-3-methyl- 6-methoxy- Ex 632 MS (ion spray)4-oxo-5H-isoxazolo[4,3- pyridine-2- 481 (M⁺). c]quinolin-5-yl))cyclo-carboxylic acid hexyl]methyl}(6-methoxy(2- pyridyl))carboxamide 231Cis-N-[3-(9-Chloro-3-methyl- prep 3 Ex 632 MS (ion spray)4-oxo-5H-isoxazolo[4,3- 481 (M⁺). c]quinolin-5-yl)cyclo- hexylmethyl]-5-methoxynicotinamide 232 cis-N-[3-(9-Chloro-3-methyl- (d/l)-2,3- Ex 634MS (ion spray) flash chrom. 4-oxo-5H-isoxazolo[4,3- difluoroman- 502(M⁺). (silica gel: 0- c]-quinolin-5-yl)cyclo- delic acid 0.5% MeOH/hexyl]-2-(2,3-difluorophenyl)- chloroform) 2-hydroxyacetamide gave bothisomers 234 cis-N-[3-(9-Chloro-3-methyl- (dA)-3,4- Ex 634 MS (ion spray)flash chrom. 4-oxo-5H-isoxazolo[4,3- difluoroman- 502 (M⁺). (silica gel:0- c]quinolin-5-yl)-cyclo- delic acid 0.5% MeOH/hexyl]-2-(3,4-difluorophenyl)- chloroform) 2-hydroxyacetamide gave bothisomers 235 cis {[3-(9-Chloro-3-methyl- N-(t-butoxy- Ex 634 MS(ES):silica gel 4-oxo-5H-isoxazolo[4,3- carbonyl)-D- (M + Na)⁺ 587.1 columneluted c]quinolin-5-yl)cyclo- phenyl-glycine m/z, (M − BOC)⁺ with 30%hexylcarbamoyl]phenylmethyl}- 465.1 m/z ethylacetate/ carbamic hexanes:acid t-butylester isomer 1 R_(t) = 33.67 min. isomer 2: R_(t) = 23.81min. Chiracel AD. 236 N-{[3-(9-Chloro-3-methyl- trimethyl-acetic Ex 633MS(ES): 4-oxo-5H-isoxazolo[4,3- acid (M + 1)⁺ 549.1,c]quinolin-5-yl)cyclo- 551.1 m/z. hexylcarbamoyl]phenylmethyl}-2,2-dimethyl-propionamide 237 N-{[3-(9-Chloro-3-methyl- nicotinic acidEx 633 MS(ES): 4-oxo-5H-isoxazolo[4,3- (M + 1)⁺ 570.0,c]quinolin-5-yl)cyclo- 572.0 m/z hexylcarbamoyl]phenylmethyl}-nicotinamide 238 Pyridine-2-carboxylic picolinic acid Ex 633 MS(ES):acid {[3-(9-chloro-3-methyl- (M + 1)⁺ 570.2, 4-oxo-5H-isoxazolo[4,3-572.3 m/z c]quinolin-5-yl)cyclo- hexylcarbamoyl]- phenylmethyl}amide 239N-{[3-(9-Chloro-3-methyl- isonicotinic Ex 633 MS(ES):4-oxo-5H-isoxazolo[4,3- acid (M + 1)⁺ 570.3, c]quinolin-5-yl)cyclo-572.3 m/z hexylcarbamoyl]phenylmethyl}- isonicotinamide 2402-t-Butylamino-N-[3-(9-chloro- prep 11 Ex 634 MS(ES): Isomer 13-methyl-4-oxo-5H-isoxazolo[4,3- (M + 1)⁺ 521.2, 38%c]quinolin-5-yl)cyclohexyl]- 522.2, 523.2 m/z 2-phenylacetamide 2412-t-Butylamino-N-[3-(9-chloro- prep 11 Ex 634 MS(ES): Isomer 23-methyl-4-oxo-5H-isoxazolo[4,3- (M + 1)⁺ 521.2, 30%c]quinolin-5-yl)cyclohexyl]- 522.2, 523.2 m/z 2-phenylacetamide 242N-[3-(9-Chloro-3-methyl-4-oxo- prep 13 Ex 634 MS(ES): Isomer 15H-isoxazolo[4,3- (M + 1)⁺ 535.3, 29% c]quinolin-5-yl)cyclohexyl]-536.3, 537.3 2-(2,2-dimethylpropylamino)-2- m/z. phenylacetamide 243N-[3-(9-Chloro-3-methyl-4-oxo- prep 13 Ex 634 MS(ES): Isomer 25H-isoxazolo[4,3-c]quinolin- (M + 1)⁺ 535.3, 44% 5-yl)cyclohexyl]-536.3, 537.3 2-(2,2-dimethylpropylamino)-2- m/z. phenylacetamide 244N-[3-(9-Chloro-3-methyl-4-oxo- nicotinic Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- acid- 467.2 (M+). 5-yl)cyclohexylmethyl]-N-oxide 1-oxynicotinamide 245 6-Amino-N-[3-(9-Chloro-3-methyl- 4-amino-Ex 619 MS (ion spray) 4-oxo-5H-isoxazolo[4,3- nicotinic acid 466.3 (M+).c]quinolin-5-yl)-cyclo- hexylmethyl]-nicotinamide 246N-[3-(9-Chloro-3-methyl-4-oxo- 3-pyridylacetic Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- acid HCl 465.0 (M+).5-yl)-cyclohexylmethyl]- 2-pyridin-3-yl-acetamide 247Quinoline-3-carboxylic 3-quinoline- Ex 619 MS (ion spray) acid[3-(9-chloro-3-methyl- carboxylic acid 501 (M+). 4-oxo-5H-isoxazolo[4,3-c]-quinolin-5-yl)cyclo- hexylmethyl]amide 248N-[3-(9-Chloro-3-methyl-4-oxo- 6-(1H-pyrazol- Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- l-yl)-nicotinic 517.2 (M+).5-yl)-cyclohexylmethyl]- acid 6-pyrazol-1-yl-nicotinamide 249N-[3-(9-Chloro-3-methyl-4-oxo- 3-pyridylpro- Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- pionic acid 479.1 (M+).5-yl)-cyclohexylmethyl]- 3-pyridin-3-yl-propionamide 250N-[3-(9-Chloro-3-methyl-4-oxo- 6-trifluoro- Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- methynicotinic 501 (M+).5-yl)-cyclohexylmethyl]- acid 6-trifluoromethyl-nicotinamide 2515-Amino-N-[3-(9-chloro-3-methyl- 5- Ex 619 MS (ion spray)4-oxo-5H-isoxazolo[4,3- aminomcotinic 466.2 (M+). c]quinolin-5-yl)- acidcyclohexylmethyl]-nicotinamide 252 Pyrimidine-5-carboxylic prep 15 Ex619 MS (ion spray) acid [3-(9-chloro-3-methyl- 452.2 (M+).4-oxo-5H-isoxazolo[4,3-c]- quinolin-5-yl)-cyclo- hexylmethyl]-amide 253N-[3-(9-Chloro-3-methyl- 4-(methyl- Ex 619 MS (ion spray)4-oxo-5H-isoxazolo[4,3- amino)benzoic 479.0 (M+).c]quinolin-5-yl)-cyclo- acid hexylmethyl]- 4-methylaminobenzamide 2546-Methyl-pyridine-2-carboxylic 6-methyl- Ex 619 MS (ion spray) acid[3-(9-chloro-3-methyl- picolinic acid 465.0 (M+).4-oxo-5H-isoxazolo[4,3-c]- quinolin-5-yl)cyclo- hexylmethyl]amide 2554-Chloro-pyridine-2-carboxylic 4-chloro- Ex 619 MS (ion spray) acid[3-(9-chloro-3-methyl- picolinic acid 486.9 (M+).4-oxo-5H-isoxazolo[4,3- (TCI-US) c]quinolin-5-yl)cyclo-hexylmethyl]amide 256 2,6-Dichloro-N-[3-(9-chloro- 2,6-dichloro- Ex 619MS (ion spray) 3-methyl-4-oxo-5H- isonicotinic 518.9 (M+).isoxazolo[4,3-c]quinolin-5-yl)- acid cyclohexylmethyl]-isonicotinamide257 N-[3-(9-Chloro-3-methyl-4-oxo- 2-fluoro- Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- isonicotinic 469.0 (M+).5-yl)-cyclohexyl-methyl]-2- acid fluoroisonicotinamide 258Furo[3,2-b]pyridine-5- Furo[3,2-b]- Ex 619 MS (ion spray) carboxylicacid[3-(9-chloro- pyridine-5- 491.2 (M+). 3-methyl-4-oxo-5H-isoxazolocarboxylic acid [4,3-c]quinolin-5- yl)cyclohexylmethyl]-amide 2596-Chloro-pyridine-2-carboxylic 6-chloro-2- Ex 619 MS (ion spray) acid[3-(9-chloro-3-methyl-4-oxo- pyridinecar- 485.2 (M+).5H-isoxazolo[4,3-c]quinolin- boxylic acid 5-yl)cyclohexylmethyl]-(SALOR) amide 260 6-Methoxy-pyridine-2-carboxylic prep 16 Ex 619 MS (ionspray) acid [3-(9-chloro-3-methyl-4-oxo- 481.1 (M+).5H-isoxazolo[4,3-c]quinolin- 5-yl)cyclohexylmethyl]amide 2614-Methoxypyridine-2-carboxylic 4-methoxy- Ex 619 MS (ion spray) acid[3-(9-chloro-3-methyl-4-oxo- picolinic acid 481.2 (M+).5H-isoxazolo[4,3-c]quinolin- HCL 5-yl)cyclohexylmethyl]amide 2625,6-Dichloro-N-[3-(9-chloro- 5,6-dichloro- Ex 619 MS (ion spray)3-methyl-4-oxo-5H-isoxazolo[4,3- nicotinic acid 519.0 (M+).c]quinolin-5-yl)- cyclohexymethyl]-nicotinamide 2632-Chloro-N-[3-(9-chloro-3-methyl- 2-chloro-6- Ex 619 MS (ion spray)4-oxo-5H-isoxazolo[4,3- methylpyridine- 498.8, 500.87c]quinolin-5-yl)cyclo- 4-carboxylic (M+). hexylmethyl]-6- acidmethylisonicotinamide 264 N-[3-(9-Chloro-3-methyl-4-oxo- 5-methyl- Ex619 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- nicotinic acid 465.1(M+). 5-yl)-cyclohexyl-methyl]-5- methyl-nicotinamide 265N-[3-(9-Chloro-3-methyl-4-oxo- prep 19 Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 481.0 (M+). 5-yl)-cyclohexyl-methyl]-6-methoxy-nicotinamide 266 5-Chloro-N-[3-(9-chloro-3- 5-chloro- Ex 619 MS(ion spray) methyl-4-oxo-5H- nicotinic acid 485.0 (M+).isoxazolo[4,3-c]quinolin- 5-yl)-cyclohexylmethyl]- nicotinamide 267N-[3-(9-Chloro-3-methyl-4-oxo- phenylacetic Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- acid 501 (M+). 5-yl)-cyclohexylmethyl]-2-phenylacetamide 268 4-Fluoronaphthalene-1-carboxylic 4-fluoro-l- Ex619 MS (ion spray) acid [3-(9-chloro-3-methyl-4-oxo- naphthoic acid518.1 (M+). 5H-isoxazolo[4,3-c]quinolin- 5-yl)cyclohexylmethyl]-amide269 N-[3-(9-Chloro-3-methyl-4-oxo- 2-methyl-3- Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- hydroxy- 479.9 (M+).5-yl)-cyclohexylmethyl]- benzoic acid 3-hydroxy-2-methylbenzamide 270N-[3-(9-Chloro-3-methyl-4-oxo- .(S)-(+)-α- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- methoxyphenyl 480.1 (M+).5-yl)-cyclohexyl]-2- acetic acid methoxy-2-phenylacetamide 271N-[3-(9-Chloro-3-methyl-4-oxo- (R)-(−)-α- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- methoxyphenyl 480.1 (M+).5-yl)cyclohexyl]-2- acetic acid methoxy-2-phenylacetamide 272N-[3-(9-Chloro-3-methyl-4-oxo- (S)-(−)-α-meth- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- oxy-α- 548.1 (M+). 5-yl)cyclohexyl]-3,3,3-(trifluoro- trifluoro-2-methoxy-2-phenyl- methyl)phenyl- propionamideacetic acid 273 Acetic acid [3-(9-chloro-3- (R)-(−)-O- Ex 634 MS (ionspray) methyl-4-oxo-5H-isoxazolo[4,3- acetyl- 508.1 (M+).c]quinolin-5-yl)cyclohexyl- mandelic acid carbamoyl]phenylmethyl ester274 Acetic acid [3-(9-chloro-3- (S)-(+)-O- Ex 634 MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3- acetyl- 508.1 (M+).c]quinolin-5-yl)cyclohexyl- mandelic acid carbamoyl]phenylmethyl ester275 N-[3-(9-Chloro-3-methyl-4-oxo- phenoxyphenyl- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- acetic acid 542.1 (M+).5-yl)-cyclohexyl]-2- phenoxy-2-phenylacetamide 276{[3-(9-Chloro-3-methyl-4-oxo- CBZ-D(−)- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- phenylglycine 599.2 (M+).5-yl)cyclohexylcarbamoyl]- phenylmethyl}carbamic acid benzyl ester 277{[3-(9-Chloro-3-methyl-4-oxo- Z-Phg-OH Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 599.2 (M+) 5-yl)cyclohexylcarbamoyl]-phenylmethyl}carbamic acid benzyl ester 278N-[3-(9-Chloro-3-methyl-4-oxo- Morpholin-4- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- yl-phenylacetic 535.2 (M+)5-yl)cyclohexyl]-2- acid morpholin-4-yl-2-phenylacetamide 2792-(Acetyl-methyl-amino)- (acetymethyl- Ex 634 MS (ion spray)N-[3-(9-chloro-3-methyl-4-oxo- amino)phenyl- 521.2 (M+)5H-isoxazolo[4,3-c]- acetic acid quinolin-5-yl)cyclohexyl]-2-phenylacetamide 280 N-[3-(9-Chloro-3-methyl-4-oxo- phenylphenyl- Ex 634MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- aminoacetic 541.1 (M+)5-yl)cyclohexyl]-2-phenyl- acid 2-phenylaminoacetamide 281N-[3-(9-Chloro-3-methyl-4-oxo- dimethylarnino- Ex 634 MS (ion spray)diastereomers 5H-isoxazolo[4,3-c]quinolin- phenylacetic 493.0 (M+) were5-yl)-cyclohexyl]-2- acid separated dimethylamino-2-phenyl-acetamide 282N-[3-(9-Chloro-3-methyl-4-oxo- phenylthio- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- morpholin-4- 550.9 (M+) 5-yl)cyclohexyl]-2-ylacetic acid phenyl-2-thiomorpholin-4-ylacetamide 283N-[3-(9-Chloro-3-methyl-4-oxo- (4-methyl- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- piperazin-1- 548.2 (M+) 5-yl)cyclohexyl]-yl)phenyl- 2-(4-methylpiperazin-1-yl)-2- acetic acid phenylacetamide 2842-(4-Acetylpiperazin-1-yl)- (4-acetyl-pip- Ex 634 MS (ion spray)N-[3-(9-chloro-3-methyl-4-oxo- erazin-1-yl)- 576.2 (M+)5H-isoxazolo[4,3-c]quinolin- phenylacetic 5-yl)cyclohexyl]-2-phenyl-acid acetamide 285 N-[3-(9-Chloro-3-methyl-4-oxo- (indan-2-yl- Ex 634 MS(ion spray) diastereomers 5H-isoxazolo[4,3-c]quinolin- amino)- 581.0(M+) were 5-yl)cyclohexyl]-2- phenylacetic separated(indan-2-ylamino)-2-phenylacetamide acid 286N-[3-(9-Chloro-3-methyl-4-oxo- (S)-(+)-2- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- hydroxy-2- 480.13 (M+)5-yl)cyclohexyl]-2-hydroxy- phenylpropionic 2-phenylpropionamide acid287 N-[3-(9-Chloro-3-methyl-oxo- (R)-(−)-2- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- hydroxy-2- 480.1 (M+)5-yl)-cyclohexyl]-2-hydroxy- phenylpropionic 2-phenyl-propionamide acid288 N-[3-(9-Chloro-3-methyl-4-oxo- m-methoxy- Ex 634 MS (ion spray)diastereomers 5H-isoxazolo[4,3-c]quinolin- mandelic acid 496.1 (M+) were5-yl)cyclohexyl]-2-hydroxy- separated 2-(3-methoxyphenyl)acetamide 289N-[3-(9-Chloro-3-methyl-4-oxo- p-methoxy- Ex 634 MS (ion spray)diastereomers 5H-isoxazolo[4,3-c]quinolin- mandelic acid 496.1 (M+) were5-yl)cyclohexyl]-2-hydroxy- separated 2-(4-methoxyphenyl)acetamide 290N-[3-(9-Chloro-3-methyl-4-oxo- p-trifluoro- Ex 634 MS (ion spray)diastereomers 5H-isoxazolo[4,3-c]quinolin- methylmandelic 534.0 (M+)were 5-yl)cyclohexyl]-2-hydroxy- acid separated2-(4-trifluoromethylphenyl)- acetamide 291N-[3-(9-Chloro-3-methyl-4-oxo- D-3-phenyl- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- lactic acid 480.2 (M+)5-yl)cyclohexyl]-2-hydroxy- 3-phenylpropionamide 292N-[3-(9-Chloro-3-methyl-4-oxo- L-3-phenyl- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- lactic acid 480.0 (M+)5-yl)-cyclohexyl]-2-hydroxy- 3-phenyl-propionamide 293N-[3-(9-Chloro-3-methyl-4-oxo- DL-tropic Ex 634 MS (ion spray)diastereomers 5H-isoxazolo[4,3-c]quinolin- acid 480.1 (M+). were5-yl)-cyclohexyl]-3-hydroxy- separated 2-phenyl-propionamide 294N-[3-(9-Chloro-3-methyl-4-oxo- (R)-(−)-3- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- chloro- 500.1 (M+) 5-yl)-cyclohexyl]-2-(3-mandelic acid chloro-phenyl)-2-hydroxyacetamide 295N-[3-(9-Chloro-3-methyl-4-oxo- racemic 3- Ex 634 MS (ion spray)diastereomers 5H-isoxazolo[4,3-c]quinolin- chloromandelic 500.1 (M+)were 5-yl)-cyclohexyl]-2-(3- acid separated bychloro-phenyl)-2-hydroxyacetamide radial EDPLC 296N-[3-(9-Chloro-3-methyl-4-oxo- hydroxy-m- Ex 634 MS (ion spray)diastereomers 5H-isoxazolo[4,3-c]quinolin- tolylacetic acid 480.0 (M+)were 5-yl)-cyclohexyl]- separated 2-hydroxy-2-m-tolylacetamide 297N-[3-(9-Chloro-3-methyl-4-oxo- (2-Fluoro- Ex 634 MS (ion spray)diastereomers 5H-isoxazolo[4,3-c]quinolin- phenyl)- 480.0 (M+) were5-yl)-cyclohexyl]-2-(2- hydroxy-acetic separatedfluoro-phenyl)-2-hydroxyacetamide acid 298N-[3-(9-Chloro-3-methyl-4-oxo- benzylic acid Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 542 (M+) 5-yl)-cyclohexyl]-2-hydroxy-2,2-diphenylacetamide 299 N-[3-(9-Chloro-3-methyl-4-oxo-dimethylphenyl Ex 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- aceticacid 478.1 (M+) 5-yl)cyclohexyl]-2-phenyliso- butyramide 3001-Phenylcyclopropanecarboxylic 1-phenyl-l- Ex 634 MS (ion spray) acid[3-(9-chloro-3-methyl-4-oxo- cyclopropyl- 476.1 (M+)5H-isoxazolo[4,3-c]- acetic acid quinolin-5-yl)cyclohexyl]amide 301N-[3-(9-Chloro-3-methyl-4-oxo- α-fluoro- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- phenylacetic 468.1 (M+) 5-yl)cyclohexyl]-2-acid fluoro-2-phenylacetamide 302 N-[3-(9-Chloro-3-methyl-4-oxo-difluorophenyl- Ex 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin-acetic acid 486.1 (M+) 5-yl)cyclohexyl]-2,2- difluoro-2-phenylacetamide303 N-[3-(9-Chloro-3-methyl-4-oxo- phenylphenylth- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- ioacetic acid 558.0 (M+).5-yl)-cyclohexyl]-2- (Lancaster) phenyl-2-phenylsulfanyl-acetamide 304N-[3-(9-Chloro-3-methyl-4-oxo- (R)-(−)-2- Ex 634 (ion spray)5H-isoxazolo[4,3-c]quinolin- phenyl- 464.2 (M+) 5-yl)-cyclohexyl]-2-propionic acid phenyl-propionamide 305 N-[3-(9-Chloro-3-methyl-4-oxo-(S)-(+)-2- Ex 634 MS (ion spray) 5H-isoxazolo[43-c]quinolin-phenylpropionic 464.2 (M+) 5-yl)cyclohexyl]-2- acid phenylpropionamide306 1-Phenylcyclohexanecarboxylic 1-phenyl-l- Ex 634 MS (ion spray) acid[3-(9-chloro-3-methyl-4-oxo- cyclohexane 518.2 (M+)5H-isoxazolo[4,3-c]quinolin- carboxylic acid 5-yl)cyclohexyl]amide(Acros) 307 N-[3-(9-Chloro-3-methyl-4-oxo- α-S-methyl- Ex 634 MS (ionspray) 5H-isoxazolo[4,3-c]quinolin- phenylacetic 495.9 (M+)5-yl)cyclohexyl]-2- acid methylsulfanyl-2-phenylacetamide 308Bicyclo[4.2.0]octa- 1-benzocyclo- Ex 634 MS (ion spray)1(6),2,4-triene-7- butenecarboxylic 461.9 (M+) carboxylic acid[3-(9-chloro- acid 3-methyl-4-oxo-5H- isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]amide 309 {2-[3-(9-Chloro-3-methyl-4-oxo- N-BOC-2- Ex 634 MS(ion spray) 5H-isoxazolo[4,3-c]quinolin- arrdnoindane-2- 491 (M − BOC)5-yl)cyclohexylcarbamoyl]indan- carboxylic acid 2-yl}carbamicacidt-butyl ester 310 3-oxo-indan-1-carboxylic 3-oxo-l- Ex 634 MS (ionspray) acid [3-(9-chloro-3-methyl-4-oxo- indancar- 489.9 (M+)5H-isoxazolo[4,3-c]quinolin- boxylic acid 5-yl)cyclohexyl]amide 3113-(9-Chloro-3-methyl-4-oxo- N-t-BOC-L- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 1,2,3,4-tetra- 591.2 (M+)5-yl)-cyclohexylcarbamoyl]-3,4- hydroisoquino-dihydro-1H-isoquinoline-2- line-3- carboxylic acid t-butyl estercarboxylic acid (Sigma) 312 3-(9-Chloro-3-methyl-4-oxo- N-t-BOC-D- Ex634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 1,2,3,4- 591.3 (M+)5-yl)-cyclohexylcarbamoyl]-3,4- tetrahydro- dihydro-1H-isoquinoline-2-isoquinoline-3- carboxylic acid t-butyl ester carboxylic acid (BAChem)313 N-[3-(9-Chloro-3-methyl-4-oxo- 6-fluoro- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- nicotinic acid 455.0 (M+)5-yl)-cyclohexyl]- 6-fluoronicotinamide 3143-[3-(9-Chloro-3-methyl-4-oxo- BOC-azetidine- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 3-carboxylic 415.08 (M+−5-yl)cyclohexylcarbamoyl]- acid BOC). azetidine-1-carboxylic acidt-butyl ester 315 2-[3-(9-Chloro-3-methyl-4-oxo- N-t-BOC-D- Ex 634 MS(ion spray) 5H-isoxazolo[4,3-c]quinolin- proline 529.2 (M+).5-yl)cyclohexyl-carbamoyl]- pyrrolidine-1-carboxylic acid t-butyl ester316 N-[3-(9-Chloro-3-methyl-4-oxo- (S)-(+)-2- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin-5- hydroxy-3,3- 446.2 (M+)yl)-cyclohexyl]-2- dimethyl- hydroxy-3,3-dimethyl-butyramide butyricacid 317 N-[3-(9-Chloro-3-methyl-4-oxo- (L)-(+)- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- hexahydro- 472.2 (M+) 5-yl)-cyclohexyl]-2-mandelic acid cyclohexyl-2-hydroxyacetamide 318N-[3-(9-Chloro-3-methyl-4-oxo- (R)-(−)- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- hexahydro- 472.2 (M+) 5-yl)-cyclohexyl]-2-mandelic acid cyclohexyl-2-hydroxyacetamide 319N-[3-(9-Chloro-3-methyl-4-oxo- 3,3,3-trifluoro- Ex 634 MS (ion spray)diastereomers 5H-isoxazolo[4,3-c]quinolin- lactic acid 480.0 (M+) were5-yl)-cyclohexyl]-3,3,3- separated trifluoro-2-hydroxy-propionamide 320N-[3-(9-Chloro-3-methyl-4-oxo- 2-methyllactic Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- acid 417.9 (M+)5-yl)-cyclohexyl]-2-hydroxy- 2-methyl-propionamide 321[1-({[3-(9-chloro-3-methyl-4-oxo- N-t-butyl-cx- Ex 638 MS(ES) [M + H]⁺ =5H-isoxazolo[4,3-c]quinolin- aminoiso- 650.2 m/z5-yl)-cyclohexyl-carbamoyl]- butryic phenylmethyl}-carbamoyl)-1- acidmethylethyl]-carbamic acid t-butylester 322 Pyridine-2-carboxylicpyridine-2- Ex 638 MS(ES) [M + H]⁺ = acid {[3-(9-chloro-3-methyl-carboxylic 570.2 m/z 4-oxo-5H-isoxazolo[4,3-c]- acidquinolin-5-yl)-cyclohexyl- carbamoyl]-phenyl-methyl}-amide 323Pyridine-3-carboxylic pyridine-3- Ex 638 MS(ES) [M + H]⁺ = acid{[3-(9-chloro- carboxylic 570.2 m/z 3-methyl-4-oxo-5H-isoxazolo[4,3-acid c]-quinolin-5-yl)-cyclohexyl- carbamoyl]-phenyl-methyl}-amide 324Pyridine-4-carboxylic pyridine-4- Ex 638 MS(ES) [M + H]⁺ = acid{[3-(9-chloro-3-methyl-4- carboxylic 570.2 m/z oxo-5H-isoxazolo[4,3-c]-acid quinolin-5-yl)-cyclohexyl- carbamoyl]-phenyl-methyl}-amide 325N-[3-(9-chloro-3-methyl-4-oxo- 2-Methyl-2- Ex 634 MS(ES) exact5H-isoxazolo[4,3-c]quinolin- [1,2,4]- mass calc'd: 5-yl)-cyclohexyl]-2-triazol-1- [M + H]⁺ = [1,2,4]triazol-1-yl- yl-propionic 469.1755 m/z.isobutyramide acid 326 {[3-(9-chloro-3-methyl-4-oxo- t-butoxy- Ex 634MS(ES) calc'd: 5H-isoxazolo[4,3-c]quinolin- carbon- [M + H]⁺ =5-yl)-cyclohexylcarbamoyl]- ylamino- 565.20 m/z;pyridin-3-yl-methyl}-carbamic pyridin- [M + Na]⁺ = acid t-butyl ester3-ylacetic 588.20 m/z. acid 327 N-[3-(9-Chloro-3-methyl-4-oxo- glycolicEx 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- acid 389.9 (M+)5-yl)-cyclohexyl]-2-hydroxy- racemic cis acetamide 328N-[3-(9-Chloro-3-methyl-4-oxo- D-alpha- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- hydroxyiso- 431.9 (M+) 5-yl)-cyclohexyl]-valeric racemic cis 2-hydroxy-3-methyl-butyramide acid 329N-[3-(9-Chloro-3-methyl-4-oxo- (S)-3-hydroxy- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 3- 480.1 (M+)5-yl)-cyclohexyl]-3-hydroxy-3- phenyl- racemic cis phenyl-propionamidepropionic acid 330 N-[3-(9-Chloro-3-methyl-4-oxo- (R)-3-hydroxy- Ex 634MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 3-phenyl- 480.1 (M+)5-yl)-cyclohexyl]-3-hydroxy-3- propionic racemic cis phenyl-propionamideacid 331 N-[3-(9-Chloro-3-methyl-4-oxo- (S)-(+)-2- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- hydroxy-3- 431.9 (M+)5-yl)-cyclohexyl]-2-hydroxy-3- methyl- racemic cis methylbutyramidebutryric acid 332 1-Hydroxy-cyclopropanecarboxylic 1-hydroxy-l- Ex 634MS (ion spray) acid [3-(9-chloro-3-methyl-4-oxo- cyclopropane- 416.0(M+) 5H-isoxazolo[4,3-c]quinolin- carboxylic racemic cis5-yl)-cyclohexyl]-amide acid 333 {[3-(9-Chloro-3-methyl-4-oxo- N-t-BOC-Ex 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- sarcosine 503.2 (M+)5-yl)-cyclohexylcarbamoyl]- racemic cis methyl}-methyl-carbamic acidt-butyl ester 334 N-[3-(9-Chloro-3-methyl-4-oxo- N,N-dimethyl- Ex 634 MS(ion spray) 5H-isoxazolo[4,3-c]quinolin- glycine 416.9 (M+)5-yl)-cyclohexyl]-2-dimethylamino- racemic cis acetamide 335{1-[3-(9-Chloro-3-methyl-4-oxo- N-t-BOC-α- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- aminoiso- 516.9 (M+)5-yl)-cyclohexylcarbamoyl]-1- butyric acid racemic cismethyl-ethyl}-carbamic acid t-butyl ester 336{[3-(9-Chloro-3-methyl-4-oxo- N-t-butoxycar- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- bonylglycine 489.1 (M+)5-yl)-cyclohexylcarbamoyl]- racemic cis methyl}-carbamic acid t-butylester 337 2-Hydroxy-hexanoic acid [3-(9- 2-hydroxy- Ex 634 MS (ionspray) diastereomers chloro-3-methyl-4-oxo-5H- caproic acid 446.2 (M+)were isoxazolo[4,3-c]quinolin-5-yl)- racemic cis separatedcyclohexyl]-amide 338 N-[3-(9-Chloro-3-methyl-4-oxo- salicylic acid Ex634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 452.0 (M+)5-yl)-cyclohexyl]-2- racemic cis hydroxybenzamide 3394-{[3-(9-Chloro-3-methyl-4-oxo- prep 285 Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 633.9 (M+)5-yl)-cyclohexylcarbamoyl]-phenyl- racemic cismethyl}-piperazine-1-carboxylic acid t-butyl ester 340{[3-(9-Chloro-3-methyl-4-oxo- BOC-N-Me- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- Phg-OH 578.9 (M+)5-yl)-cyclohexylcarbamoyl]- racemic cis phenyl-methyl}-methyl- carbamicacid t-butyl ester 341 N-[3-(9-Chloro-3-methyl-4-oxo- prep 287 Ex 634 MS(ion spray) diastereomers 5H-isoxazolo[4,3-c]quinolin- 578.1 (M+) were5-yl)-cyclohexyl]-2-[4-(2- racemic cis separatedhydroxy-ethyl)-piperazin-1-yl]-2- phenyl-acetaniide 342N-[3-(9-Chloro-3-methyl-4-oxo- prep 288 Ex 634 MS (ion spray)diastereomers 5H-isoxazolo[4,3-c]quinolin- 610.9 (M+) were5-yl)-cyclohexyl]-2-phenyl-2-(4- racemic cis separatedpyridin-2-yl-piperazin-1-yl)- acetamide 343N-[3-(9-Chloro-3-methyl-4-oxo- prep 290 Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 457.1 (M+) 5-yl)-cyclohexyl]-2- racemic cispiperidin-1-yl-acetamide 344 N-[3-(9-Chloro-3-methyl-4-oxo- prep 292 Ex634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 472.0 (M+)5-yl)-cyclohexyl]-2-(4- racemic cis methyl-piperazin-1-yl)-acetamide 345N-[3-(9-Chloro-3-methyl-4-oxo- N,N-diethyl- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- glycine 445.0 (M+) 5-yl)-cyclohexyl]-2-sodium diethylamino-acetamide salt 346 N-[3-(9-Chloro-3-methyl-4-oxo-prep 293 Ex 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 479.0 (M+)5-yl)-cyclohexyl]-2- racemic cis (methyl-phenyl-amino)-acetamide 347N-[3-(9-Chloro-3-methyl-4-oxo- prep 294 Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 543.0 (M+) 5-yl)-cyclohexyl]-2-phenyl-2-(pyridin-3-yloxy)-acetamide 348 N-[3-(9-Chloro-3-methyl-4-oxo- prep296 Ex 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 467.1 (M+)5-yl)-cyclohexyl]-2-(pyridin- 3-yloxy)-acetamide 349{1-[3-(9-Chloro-3-methyl-4-oxo- prep 297 Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 557.2 (M+) 5-yl)-cyclohexylcarbamoyl]-cyclohexyl}carbamic acid t- butyl ester 350N-[3-(9-Chloro-3-methyl-4-oxo- prep 299 Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 459.0 (M+) 5-yl)-cyclohexyl]-2-morpholin-4-yl-acetamide 351 N-[3-(9-Chloro-3-methyl-4-oxo- prep 301 Ex634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 473.1 (M+)5-yl)-cyclohexyl]-2-(4- hydroxy-piperidin-1-yl)-acetamide 352N-[3-(9-Chloro-3-methyl-4-oxo- prep 303 Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 467.1 (M+) 5-yl)-cyclohexyl]-2-(2-oxo-2H-pyridin-1-yl)-acetamide 353 N-[3-(9-Chloro-3-methyl-4-oxo- prep304 Ex 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 467.0 (M+)5-yl)-cyclohexyl]-2- (pyridin-4-yloxy)-acetamide 354N-[3-(9-Chloro-3-methyl-4-oxo- (4-pyridyl- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- thio)- 483.1 (M+) 5-yl)-cyclohexyl]-2-acetic (pyridin-4-ylsulfanyl)-acetamide acid 355{[3-(9-Chloro-3-methyl-4-oxo- N-t-BOC-D-α- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- cyclohexyl- 571.2 (M+)5-yl)-cyclohexylcarbamoyl]- glycine cyclohexyl-methyl}-carbamic acidt-butyl ester 356 {[3-(9-Chloro-3-methyl-4-oxo- N-t-BOC-L-α- Ex 634 MS(ion spray) 5H-isoxazolo[4,3-c]quinolin- cyclohexyl- 571.2 (M+)5-yl)-cyclohexylcarbamoyl]- glycine cyclohexyl-methyl}-carbamic acidt-butyl ester 357 Thieno[3,2-b]pyridine-2- thieno[3,2-b]- Ex 634 MS (ionspray) carboxylic acid[3-(9-chloro-3- pyridine-2- 493.0 (M+).methyl-4-oxo-5H-isoxazolo[4,3- carboxylic acidc]quinolin-5-yl)-cyclohexyl]- amide 358 N-[3-(9-Chloro-3-methyl-4-oxo-thieno[3,2-b]- Ex 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin-pyridine-2- 501.0 (M+) 5-yl)-cyclohexyl]-2-(2- carboxylic acidchloro-pyridin-4-yloxy)-acetamide 359 N-[3-(9-Chloro-3-methyl-4-oxo-(quinolin-3- Ex 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin-yloxy)acetic 517.2 (M+) 5-yl)-cyclohexyl]-2- acid HCl(quinolin-3-yloxy)-acetamide (SALOR) 3602-t-Butylamino-N-[3-(9-chloro-3- prep 305 Ex 634 MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3- 445.1 (M+) c]quinolin-5-yl)-cyclohexyl]-acetamide 361 N-[3-(9-Chloro-3-methyl-4-oxo- (pyridin-2- Ex 634 MS (ionspray) 5H-isoxazolo[4,3-c]quinolin- ylsulfanyl)- 483.1 (M+)5-yl)-cyclohexyl]-2- acetic (pyridin-2-ylsulfanyl)-acetamide acid(Maybridge) 362 N-[3-(9-Chloro-3-methyl-4-oxo- trans-3-(3- Ex 634 MS(ion spray) 5H-isoxazolo[4,3-c]quinolin- pyridyl)- 463.1 (M+)5-yl)-cyclohexyl]-3- acrylic pyridin-3-yl-acrylamide acid 363N-[3-(9-Chloro-3-methyl-4-oxo- trans-3- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- Pyridin-2-yl- 463.1 (M+)5-yl)-cyclohexyl]-3- acrylic acid pyridin-2-yl-acrylamide 364N-[3-(9-Chloro-3-methyl-4-oxo- trans-3-(4- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- pyridyl)- 463.0 (M+) 5-yl)-cyclohexyl]-3-acrylic pyridin-4-yl-acrylamide acid 365 {1-[3-(9-Chloro-3-methyl-4-oxo-N-t-BOC-L- Ex 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- Serine519.0 (M+) 5-yl)-cyclohexylcarbamoyl]-2- hydroxy-ethyl}-carbamic acidt-butyl ester 366 {1-[3-(9-Chloro-3-methyl-4-oxo- N-t-BOC-D- Ex 634 MS(ion spray) 5H-isoxazolo[4,3-c]quinolin- Serine 519.0 (M+)5-yl)-cyclohexylcarbamoyl]-2- hydroxy-ethyl}-carbamic acid t-butyl ester367 N-[3-(9-Chloro-3-methyl-4-oxo- prep 306 Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 496.2 (M+) 5-yl)-cyclohexyl]-2(6-methoxy-pyridin-3-ylamino)-acetamide 368 N-[3-(9-Chloro-3-methyl-4-oxo- prep 307Ex 634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 481.2 (M+)5-yl)-cyclohexyl]-2- (pyridin-3-yloxy)-propionamide 369N-[3-(9-Chloro-3-methyl-4-oxo- (pyridin-2- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- yloxy) acetic 467.0 (M+)5-yl)-cyclohexyl]-2- acid (pyridin-2-yloxy)-acetamide 370{1-[3-(9-Chloro-3-methyl-4-oxo- N-BOC-L- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- phenyl- 579.2 (M+)5-yl)-cyclohexylcarbamoyl]- alanine 2-phenyl-ethyl}-carbamic acidt-butyl ester 371 N-[3-(9-Chloro-3-methyl-4-oxo- benzylic Ex 634 MS (ionspray) 5H-isoxazolo[4,3-c]quinolin- acid 542 (M+) 5-yl)-cyclohexyl]-2-hydroxy-2,2-diphenyl-acetamide 372 N-[3-(9-Chloro-3-methyl-4-oxo-9-hydroxy-9- Ex 634 MS (ion spray) 5H-isoxazol[4,3-c]quinolin- fluorene-540.1 (M+) 5-yl)-cyclohexyl]-2-(9H-fluoren- carboxylic9-yl)-2-hydroxy-acetamide acid 373 N-[3R-Chloro-3-methyl-4-oxo-6-fluoro- prep 137 MS(ES+)m/z = 4 5H-isoxazolo[4,3-c]quinolin- nicotinic83.1 5-yl)R-cycloheptyl-methyl]-6- acid fluoro-nicotinamide 3742-(Benzenesulfonyl-pyridin-2-yl- (benzenesulf- prep 137 MS (ion spray)amino)-N-[3-(9-chloro-3-methyl- onylpyridin-2- 606.1 (M+)4-oxo5H-isoxazolo[4,3- yl-amino) c]quinolin-5-yl)-cyclohexyl]- aceticacid acetamide (Bionet) 375 2-Chloro-N-[3-(9-cbloro-3-methyl- prep 3552-chloro-6- MS (ion spray) 4-oxo- meth-oxy- 514.8 (M+)5H-isoxazolo[4,3-c]quinolin- pyridine-4- 5-yl)-cyclohexylmethyl]-6-carboxylic methoxy-isonicotinamide acid 3761-Methyl-piperidine-3-carboxylic prep 355 prep 357 MS (ion spray) acid[3-(9-chloro-3-methyl-4-oxo- 471.2 (M+) 5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-amide 377 3-{[3-(9-Chloro-3-methyl-4-oxo- prep355 prep 358 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin-5- 557.2 (M+)yl)-cyclohexylmethyl]- carbamoyl}-piperidine-1- carboxylic acidtert-butyl ester 378 N-[3-(9-Chloro-3-methyl-4-oxo- prep 69 1-methyl-3-MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- indoleacetic 503.3 (M+)5-yl)-cyclohexyl]-2- acid (1-methyl-7H-indol-3-yl)-acetamide 3792-(Pyridin-3-yloxy)-hexanoic prep 362 prep 357 MS (ion spray) acid[3-(9-chloro-3-methyl-4-oxo- 523.3 (M+) 5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide 380 N-[3-(9-Chloro-3-methyl-4-oxo- prep 380R-Madelic MS (ES+) m/z 5H-isoxazolo[4,5-c]quinolin- acid 466.1 (M + H)⁺,5-yl)-cyclohexyl]-2- (ES−) 464.2 (M − hydroxy-2-phenyl-acetamide H)⁻.381 N-[3-(9-Chloro-3-methyl-4-oxo- prep 380 3-Fluoro- MS (ES+) m/z5H-isoxazolo[4,5-c]quinolin- phenylacetic 468.1 (M + H)⁺,5-yl)-cyclohexyl]-2-(3- acid (ES−) 466.2 (M − fluorophenyl)acetamide H)⁻382 N-[(1S,3R)-3-(9-Chloro-3-methyl- phenyl- Prep 44 MS (ion spray)4-oxo-5H-isoxazolo[4,3- butyric 492.2 (M+) c]quinolin-5-yl)-cyclohexyl-acid methyl]-4-phenyl-butanamide 383 N-[(1S,3R)-3-(9-Chloro-3-methyl-3-benzoyl- Prep 44 MS (ion spray) 4-oxo-5H-isoxazolo[4,3- propionic506.2 (M+) c]quinolin-5-yl)-cyclohexyl- acidmethyl]-4-oxo-4-phenyl-butanamide 384 N-[(1S,3R)-3-(9-chloro-3-methyl-3-(4-hydroxy- Prep 44 MS (ion spray) 4-oxo-5H-isoxazolo[4,3- phenyl)-494.2 (M + 1) c]quinolin-5-yl)-cyclohexyl- propionicmethyl]-3-(4-hydroxy-phenyl)- acid propanamide 385N-[(1S,3R)-3-(9-chloro-3-methyl- 3-indole- Prep 44 MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- propionic 516.9 (M+)quinolin-5-yl)cyclohexyl- acid methyl]-3-(1H-indol-3-yl)- propanamide386 N-[(1S,3R)-3-(9-chloro-3-methyl- N,N-dimethyl- Prep 44 MS (ionspray) 4-oxo-5H-isoxazolo[4,3-c]- glycine HCL 431.2 (M + 1)quinolin-5-yl)-cyclohexyl- methyl]-2-dimethylamino- acetamide 387(2R)-N-[(1S,3R)-3-(9-chloro-3- (D)-BOC- Prep 44 MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3- benzyloxy- 523.2 (M −c]quinolin-5-yl)-cyclohexyl- serine 100(M − BOC)methyl]-2-[t-butoxycarbonyl- amino]-3-(phenylmethoxy)- propanamide 388(2S)-N-[(1S,3R)-3-(9-Chloro-3- (L)-BOC- Prep 44 MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3- benzyloxy- 523.0 (M − c]quinolin-5-yl)-serine 100(M − BOC) cyclohexylmethyl]-2-[t- butoxycarbonyl-amino]-3-(phenylmethoxy)propanamide 389 2-[(1R,3S)-3-(9-Chloro-3-methyl- Prep 47cyclohexylamine MS (ion spray) 4-oxo-5H-isoxazolo[4,3- 456.2 (M + 1)c]quinolin-5-yl)-cyclo- hexyl]-N-cyclohexyl-acetamide 3902-[(1R,3S)-3-(9-Chloro-3-methyl- Prep 47 aniline MS (ion spray)4-oxo-5H-isoxazolo[4,3- 448.1 (M + 1) c]quinolin-5-yl)-cyclo-hexyl]-N-phenyl-acetamide 391 2-[(1R,3S)-3-(9-Chloro-3-methyl- Prep 472-amino- MS (ion spray) 4-oxo-5H-isoxazolo[4,3- pyridine 451.2 (M + 1)c]quinolin-5-yl)-cyclohexyl] -N-pyridin-2-yl-acetamide 3922-[(1R,3S)-3-(9-chloro-3-methyl- Prep 47 3-amino- MS (ion spray)4-oxo-5H-isoxazolo[4,3- aceto- 492.2 (M + 1)c]quinolin-5-yl)-cyclo-hexyl]- phenone N-(3-acetyl-phenyl)acetamide 3932-[(1R,3S)-3-(9-Chloro-3-methyl- Prep 47 3-methane- MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- sulf- 528.2 (M+)quinolin-5-yl)cyclohexyl]-N-(3- onylanilinemethanesulfonylphenyl)-acetamide HCL 3942-[(1R,3S)-3-(9-Chloro-3-methyl- Prep 47 4-fluoro- MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- aniline 468.2 (M + 1)quinolin-5-yl)-cyclohexyl]- N-(4-fluoro-phenyl)-acetamide 3952-[(1R,3S)-3-(9-Chloro-3-methyl- Prep 47 3-fluoro- MS (ion spray)4-oxo-5H-isoxazolo[4,3- aniline 468.2 (M + 1)c]quinolin-5-yl)-cyclohexyl]- N-(3-fluoro-phenyl)-acetamide 3962-[(1R,3S)-3-(9-Chloro-3-methyl- Prep 47 3- MS (ion spray)4-oxo-5H-isoxazolo[4,3- methoxy- 480.2 (M + 1)c]quinolin-5-yl)-cyclohexyl]- aniline N-(3-methoxy-phenyl)-acetamide 397N-[(1R,3S)-3-(9-chloro-3-methyl- (3,5- Prep 48 MS (ion spray)4-oxo-5H-isoxazolo[4,3- dimethoxy-4- 524.3 (M + 1)c]quinolin-5-yl)-cyclohexyl- methyl)- methyl]-3,5- benzoic aciddimethoxy-4-methyl-benzamide 398 N-[(1R,3S)-3-(9-chloro-3-methyl-1-methyl- Prep 48 MS (ion spray) 4-oxo-5H-isoxazolo[4,3- piperidine-4-471.2 (M + 1) c]quinolin-5-yl)-cyclohexyl- carboxylicmethyl]-1-methylpiperid-4- acid ylcarboxamide HCL 399N-[(1R,3S)-3-(9-chloro-3-methyl- 1,2,3- Prep 48 MS (ion spray)4-oxo-5H-isoxazolo[4,3- thiadiazole-4- 458.1 (M + 1)c]quinolin-5-yl)-cyclohexyl- carboxylic methyl]-[1,2,3]thiadiazol- acid4-ylcarboxamide 400 6-Chloro-N-[(1R,3S)-3-(9-chloro- 6- Prep 48 MS (ionspray) 3-methyl-4-oxo-5H-isoxazolo[4,3- chloroni- 485.1 (M+)c]quinolin-5-yl)-cyclohexyl- cotinic methyl]-nicotinamide acid 4016-Methyl-N-[(1R,3S)-3-(9-chloro- 6-methyl- Prep 48 MS (ion spray)3-methyl-4-oxo-5H-isoxazolo[4,3- nicotinic 465.1 (M + 1)c]quinolin-5-yl)cyclohexyl- acid methyl]-nicotinamide 4022-Methyl-N-[(1R,3S)-3-(9-chloro- 2-methylnicotinic Prep 48 MS (ionspray) 3-methyl-4-oxo-5H-isoxazolo[4,3- acid 465.1 (M + 1)c]quinolin-5-yl)cyclohexyl- methyl]nicotinamide 4032-Fluoro-N-[(1R,3S)-3-(9-chloro- 2- Prep 48 MS (ion spray)3-methyl-4-oxo-5H-isoxazolo[4,3- fluoroni- 469.1 (M + 1)c]quinolin-5-yl)cyclohexyl- cotinic methyl]nicotinamide acid. 404N-[(1R,3S)-3-(9-Chloro-3-methyl- 5- Prep 48 MS (ion spray)4-oxo-5H-isoxazolo[4,3- fluoroni- 469.1 (M + 1)c]quinolin-5-yl)cyclohexyl- cotinic methyl]-5-fluoro-nicotinamide acid405 N-[(1R,3S)-3-(9-Chloro-3-methyl- 2-(methylthio)- Prep 48 MS (ionspray) 4-oxo-5H-isoxazolo[4,3-c]- nicotinic 497.0 (M+)quinolin-5-yl)cyclohexylmethyl]- acid 2-methylsulfanyl-nicotinamide 4062-Chloro-N-[(1R,3S)-3-(9-chloro- 2-chloroiso- Ex 615 MS (ion spray)3-methyl-4-oxo-5H-isoxazolo[4,3- nicotinic 485.1,487.1c]quinolin-5-yl)cyclohexyl- acid (M+) methyl]isonicotine 407N-[(1R,3S)-3-(9-chloro-3-methyl- pyrazinecar- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3- boxylic 452.1 (M + 1) c]quinolin-5-yl)-cyclo-acid hexylmethyl]-pyrazin-2- yl carboxamide 408N-[(1R,3S)-3-(9-chloro-3-methyl- cinnoline-4- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3- carboxylic 502.2 (M + 1)c]quinolin-5-yl)-cyclohexyl- acid methyl]-cinnolin-4-yl carboxamide 409N-[(1R,3S)-3-(9-chloro-3-methyl- M-methyl- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- pyrrole-2- 453.2 (M + 1)quinolin-5-yl)cyclohexylmethyl]- carboxylic 1-methyl-1H-pyrrol-3-ylcarboxamide acid 410 N-[(1R,3S)-3-(9-chloro-3-methyl- 4-pyrazole- Ex 615MS (ion spray) 4-oxo-5H-isoxazolo[4,3- carboxylic 440.1 (M + 1)c]quinolin-5-yl)-cyclohexyl- acid methyl]-1H-pyrazol-4-yl carboxamide411 N-[(1R,3S)-3-(9-chloro-3-methyl- indole-3- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3- carboxylic 489.1 (M + 1)c]quinolin-5-yl)-cyclohexyl- acid methyl]-1H-indol-3-yl carboxamide 412N-[(1R,3S)-3-(9-chloro-3-methyl- indole-2- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3- carboxylic 488.1 (M+)c]quinolin-5-yl)-cyclohexyl- acid methyl]-1H-indol-2-yl carboxamide 413N-[(1R,3S)-3-(9-chloro-3-methyl- 1-methyl- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3- indole-2- 503.1 (M+)c]quinolin-5-yl)-cyclohexyl- carboxylic methyl]-1-methyl-1H-indol-2-ylacid carboxamide 414 N-[(1R,3S)-3-(9-Chloro-3-methyl- indole-4- Ex 615MS (ion spray) 4-oxo-5H-isoxazolo[4,3- carboxylic 489.1 (M+)c]quinolin-5-yl)-cyclohexyl- acid methyl]-1H-indol-4-yl carboxamide 415N-[(1R,3S)-3-(9-chloro-3-methyl- 1-methyl-4- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]- irnidazole 468 (M⁺), 466quinolin-5-yl)cyclohexylmethyl]- acetic acid (M⁻ − 1)2-(1-methyl-1H-imidazol-4- hydrochloride yl)acetamide 4163-Benzoyl-N-[(1R,3S)-3-(9-chloro-3-methyl- 3- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3- benzoyl- 554 (M+), 552 c]quinolin-5-yl)- benzoic(M⁻ − 1) cyclohexylmethyl]-benzamide acid 417N-[(1R,3S)-3-(9-chloro-3-methyl- 3- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3- phenoxy- 542 (M⁺), 540 c]quinolin-5-yl)-cyclo-benzoic (M⁻ − 1) hexylmethyl]-3-phenoxy-benzamide acid 418N-[(1R,3S)-3-(9-chloro-3-methyl- 4-methoxythio- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3- phene-3- 486 (M⁺), 484 c]quinolin-5-yl)-cyclo-carboxylic (M⁻ − 1) hexylmethyl]-4-methoxythiophen- acid 3-ylcarboxamide 419 1,2,5-Trimethyl-1H-pyrrole-3- 1,2,5- Ex 615 MS (ionspray) carboxylic acid [(1R,3S)-3-(9- trimethyl- 481 (M⁺)chloro-3-methyl-4-oxo- pyrrole- 5H-isoxazolo[4,3-c]quinolin-3-carboxylic 5-yl)-cyclohexylmethyl]-amide acid 420N-[(1R,3S)-3-(9-chloro-3-methyl- 6-Fluoro- Ex 615 MS (ion spray)4-oxo-5H-isoxazolo[4,3- nicotinic 469 (M⁺) c]quinolin-5-yl)cyclo- acidhexylmethyl]-6-fluoronicotinamide 421 2-[3-(9-chloro-3-methyl-4-oxo-Prep 63 3,4,5,- MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- trimethoxy450 (M⁺), 448 5-yl)-2,2-dimethyl-cyclobutyl]- aniline (M⁻ − 1)N-(3,4,5-trimethoxyphenyl)- acetamide 422 2-[3-(9-chloro-3-methyl-4-oxo-Prep 63 aniline MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 540 (M⁺),538 5-yl)-2,2-dimethyl-cyclobutyl]- (M⁻ − 1) N-phenylacetamide 4232-[3-(9-Chloro-3-methyl-4-oxo- Prep 63 3-amino- MS (ion spray)5H-isoxazolo[4,3-c]quinolin- pyridine 451 (M⁺),4495-yl)-2,2-dimethyl-cyclobutyl]- (M⁻ − 1) N-pyridin-3-ylacetamide 424N-[3-(9-Chloro-3-methyl-4-oxo- 3-fluoro- Prep 68 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- phenyl- 468 (M⁺), 4665-yl)cyclohexyl]-2-(3- acetic (M⁻ − 1) fluorophenyl)acetamide acid 425N-[3-(9-chloro-3-methyl-4-oxo- 3-fluoro- prep 69 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- phenyl- 468 (M⁺), 4665-yl)cyclohexyl]-2-(3- acetic (M⁻ − 1) fluorophenyl)acetamide acid 426N-[3-(9-chloro-3-methyl- 3-pyridyl- prep 69 MS (ion spray)4-oxo-5H-isoxazolo[4,3- acetic 451 (M⁺),449 c]quinolin-5-yl)cyclohexyl]-acid HCl (M⁻ − 1) 2-pyridin-3-ylacetamide 427 N-[3-(9-chloro-3-methyl-4-pyridyl- prep 69 MS (ion spray) 4-oxo-5H-isoxazolo[4,3- acetic 451(M⁺),449 c]quinolin-5-yl)cyclohexyl]- acid HCl (M⁻ − 1)2-pyridin-4-ylacetamide 428 N-[3-(9-chloro-3-methyl-4-oxo- 1-methyl-4-prep 69 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- imidazol- 454 (M+),452 5-yl)cyclohexyl]-2-(1- eacetic (M⁻ − 1)methyl-3H-imidazol-4-yl)acetamide acid HCl 4292-[3-(9-chloro-3-methyl-4-oxo- N-BOC-(S)-(−)- prep 69 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- indoline-2- 477 (M⁺ − BOC +5-yl)cyclohexylcarbamoyl]-2,3- carboxylic 1) dihydroindole-1-carboxylicacid acid t-butyl ester 430 [[3-(9-chloro-3-methyl-4-oxo- N-BOC-L-4-prep 69 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- fluoro- 483 (M⁺ −BOC + 1) 5-yl)cyclohexyl-carbamoyl]-(4- phenyl-fluorophenyl)methyl]carbamic glycine acid t-butyl ester 431N-[3-(9-Chloro-3-methyl-4-oxo- diphenylacetic prep 69 MS (ES) 526.25H-isoxazolo[4,3-c]quinolin- acid m/z[M + H]⁺ 5-yl)cyclohexyl]-2,2-diphenylacetamide 432 2-[3-(9-Chloro-3-methyl-4-oxo- prep 943,4,5-trimethoxy MS (HA) m/z = diastereomers5H-isoxazolo[4,3-c]quinolin- aniline 540.5 were5-yl]-N-3,4,5-trimethoxy- separated phenylacetamide 4333-(9-Chloro-3-methyl-4-oxo- prep 102 cyclobutylamine MS (ES+) (m/z)5H-isoxazolo[4,3-c]quinolin- 428.1 [M + 1] 5-ylmethyl)-cyclohexane-carboxylic acid cyclobutylamide 434 3-(9-Chloro-3-methyl-4-oxo- prep 102cyclohexylamine Mass Spectrum 5H-isoxazolo[4,3-c]quinolin- (FIA) (m/z)5-ylmethyl)-cyclohexane- 456.3 [M + 1] carboxylic acid cyclohexylamide435 3-(9-Chloro-3-methyl-4-oxo- prep 102 aniline MS (FIA) (m/z)5H-isoxazolo[4,3-c]quinolin- 448.1 [M − 1] 5-ylmethyl)-cyclohexane-carboxylic acid phenylamide 436 3-(9-Chloro-3-methyl-4-oxo- prep 1023-aminopyridine Mass Spectrum 5H-isoxazolo[4,3-c]quinolin- (FIA) (m/z)5-ylmethyl)-cyclohexanecarb- 451.1 [M + 1] oxylic acid pyridin-2-ylamide437 N-(3,4,5-trimethoxyphenyl)[3- prep 120 trimethoxyaniline MS (ionspray) diastereomers methyl-4-oxo-9-chloro-5H- 526.2 (M + 1) wereisoxazolo[4,3-c]quinolin- separated 5-yl)cyclohexyl]amide 4382-[3-(9-chloro-3-methyl-4-oxo- prep 145 aniline MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 450 (M⁺) 5-yl)-cyclohexyl]-N-phenyl-acetamide 439 2-[3-(9-chloro-3-methyl-4-oxo- prep 145 3-amino-MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- pyridine 450 (M⁺)5-yl)-cyclohexyl]- N-pyridin-3-yl-acetamide 4402-[3-(9-chloro-3-methyl-4-oxo- prep 145 3-Methoxy- MS (ion spray)5H-isoxazolo[4,3-c]quinolin- phenylamine 480 (M⁺) 5-yl)-cyclohexyl]-N-(3-methoxy-phenyl)-acetamide 441 N-[3-(9-Chloro-3-methyl-4-oxo-Hydroxy- prep 48 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- phenyl-543.1 (M+) 5-yl)-cyclohexyl]- pyridin-2-hydroxy-2-phenyl-2-pyridin-3-yl- 3-yl-acetic acetamide acid 442N-[3-(9-Chloro-3-methyl-4-oxo- R-Madelic prep 380 MS (ES+) m/z5H-isoxazolo[4,5-c]quinolin- acid 466.1 (M + H)+, 5-yl)-cyclohexyl]-2-(ES−) 464.2 (M − hydroxy-2-phenyl-acetamide H)− 443N-[3-(9-Chloro-3-methyl-4-oxo- S-Madelic prep 380 MS (ES+) m/z5H-isoxazolo[4,5-c]quinolin- acid 466.1 (M + H)⁺, 5-yl)-cyclohexyl]-2-(ES−) 464.2 (M − hydroxy-2-phenyl-acetamide H)⁻ 444N-[3-(9-Chloro-3-methyl-4-oxo- 3-F- prep 380 MS (ES+) m/z5H-isoxazolo[4,5-c]quinolin- Phenylacetic 468.1 (M + H)⁺,5-yl)-cyclohexyl]-2- acid (ES−) 466.2 (M − (3-fluoro-phenyl)-acetamideH)⁻ 445 N-[3-(9-Chloro-3-methyl-4- R-Madelic prep 399 MS (ES+) m/zoxo-2,4-dihydro-pyrazolo[4,3- acid 465.2 (M + H)⁺c]quinolin-5-yl)-cyclohexyl]- 2-hydroxy-2-phenyl-acetamide 446N-[3-(9-Chloro-3-methyl-4-oxo- S-Madelic prep 399 MS (ES+) m/z2,4-dihydro-pyrazolo[4,3- acid 465.2 (M + H)⁺c]quinolin-5-yl)-cyclohexyl]- 2-hydroxy-2-phenyl-acetamide 4476-Hydroxy-pyridine-2-carboxylic 6-hydroxy- prep 48 MS (ion spray) acid[3-(9-chloro-3-methyl-4- picolinic 467 (M+) oxo-5H-isoxazolo[4,3- acidc]quinolin-5-yl)cyclohexyl- methyl]- amide 448N-[3-(9-Chloro-3-methyl-4-oxo- Ex 615 prep 69 MS (ion spray) Prep 69 was5H-isoxazolo[4,3-c]quinolin- 467 (M+) hydro-lized 5-yl)-cyclohexyl]-2-by LiOH in hydroxy-2-pyridin-2-yl-acetamide dioxane at rt. 449N-[3-(9-Chloro-3-methyl-4-oxo- Ex 615 prep 69 MS (ion spray) Prep 69 was5H-isoxazolo[4,3-c]quinolin- 467 (M⁺) hydro-lized 5-yl)-cyclohexyl]-2-by LiOH in hydroxy-2-pyridin-3-yl-acetamide dioxane at rt. 450{1-[3-(9-Chloro-3-methyl-4-oxo- Ex 615 prep 69 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- 543 (M⁺) 5-yl)-cyclohexylcarbamoyl]-cyclopentyl}-carbamic acid tert- butyl ester 451{1-[3-(9-Chloro-3-methyl- Ex 615 prep 69 MS (ion spray)4-oxo-5H-isoxazolo[4,3- 515 (M⁺) c]quinolin-5-yl)-cyclohexyl-carbamoyl]-cyclopropyl}- carbamic acid tert-butyl ester 4522-Amino-bicyclo[2,2,1]heptane- Ex 615 prep 69 MS (ion spray)2-carboxylicacid [3-(9-chloro-3- 469 (M⁺) methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)- cyclohexyl]-amide 453 N-[3-(9-Chloro-3-methyl-4-oxo-Ex 615 prep 69 MS (ion spray) Prep 69 was 5H-isoxazolo[4,3-c]quinolin-613 (M⁺) hydro-lized 5-yl)-cyclohexyl]-4- by LiOH indimethylamino-2-phenoxy-2-phenyl- dioxane at rt. butyramide 454S(+)1R,3S-N-[3-(9-Chloro-3- (S)(+) Ex 621 ESMS: 466methyl-4-oxo-5H-isoxazolo[4,3- Mandelic (M + 1)⁺ c]quinolin-5-ylmethyl)-acid cyclopentyl]-2-hydroxy-2-phenyl- acetamide 455R(−)1R,3S-N-[3-(9-Chloro-3- (R)(−) Ex 621 ESMS: 466methyl-4-oxo-5H-isoxazolo[4,3- Mandelic (M + 1)⁺c]quinolin-5-ylmethyl)cyclo- acid pentyl]-2-hydroxy-2-phenyl- acetamide456 S(+)tert-Butoxycarbonylamino- S(+)N-t-BOC- prep 69 MS (ion spray)acetic acid [3-(9-chloro-3- glycine 623 (M⁺)methyl-4-oxo-5H-isoxazolo[4,3- c]quinolin-5-yl)-cyclohexyl-carbamoyl]-phenyl-methyl ester 457 R(−)tert-Butoxycarbonylamino-R(−)N-t-BOC- prep 69 MS (ion spray) acetic acid [3-(9-chloro-3- glycine623 (M⁺) methyl-4-oxo-5H-isoxazolo[4,3- c]quinolin-5-yl)-cyclohexyl-carbamoyl]-phenyl-methyl ester 458 2-(4-Acetyl-piperazin-1-yl)- prep 395prep 69 MS (exact mass) Prep 69 was N-[3-(9-chloro-3-methyl-4-oxo- [M +H]⁺ = hydro-lized 5H-isoxazolo[4,3-c]- 577.2340 m/z by LiOH inquinolin-5-yl)cyclohexyl]- dioxane at rt. 2-pyridin-3-yl- acetamide 459N-[3-(9-Chloro-3-methyl-4-oxo- prep 396 prep 69 MS(ES) [M + H]⁺ = Prep69 was 5H-isoxazolo[4,3-c]quinolin- 544.4 m/z; hydro-lized5-yl)-cyclohexyl]-2- [M − H]⁻ = by LiOH inpyridin-3-yl-2-(pyridin-2-yloxy)- 542.3 m/z dioxane at rt. acetamide 460N-[3-(9-Chloro-3-methyl-4-oxo- prep 397 prep 69 MS(ES) [M + H]⁺ = Prep69 was 5H-isoxazolo[4,3-c]quinolin- 544.3 m/z; hydro-lized5-yl)-cyclohexyl]-2-pyridin-3- [M − H]⁻ = by LiOH inyl-2-(pyridin-3-yloxy)-acetamide 542.5 m/z dioxane at rt. 461N-[3-(9-Chloro-3-methyl-4-oxo- prep 398 prep 69 MS(ES) [M + H]⁺ = Prep69 was 5H-isoxazolo[4,3-c]quinolin- 544.3 m/z; hydro-lized5-yl)-cyclohexyl]-2-pyridin-3- [M − H]⁻ = by LiOH inyl-2-(pyridin-4-yloxy)-acetamide 542.4 m/z dioxane at rt. 4624-tert-Butoxycarbonylamino-butyric Ex 471 prep 69 MS(ES)[M + H]⁺ = acid[3-(9-chloro-3-methyl-4- 651.2 m/z oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl- carbamoyl]-phenyl-methyl ester 463N-[3-(9-Chloro-3-methyl-4-oxo- Hydroxy- prep 69 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- phenyl- 543.1 (M⁺)5-yl)-cyclohexyl]-2-hydroxy- pyridin- 2-phenyl-2-pyridin-3-yl-acetamide3-yl-acetic acid 465 N-[3-(9-Chloro-3-methyl-4-oxo- 4-fluoro- Ex 634 MS(ion spray) noDMAP 5H-isoxazolo[4,3-c]quinolin-5- phenyl- 468 (M⁺)yl)-cyclohexyl]-2-(4-fluoro- acetic phenyl)acetamide acid 466N-[3-(9-Chloro-3-methyl-4-oxo- benzoyl- Ex 634 MS(ion spray)5H-isoxazolo[4,3-c]quinolin- formic 464 (M⁺). 5-yl)-cyclohexyl]-2- acidoxo-2-phenylacetamide 467 3-(9-Chloro-3-methyl-4-oxo- Prep 43benzylamine MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- 450 (M⁺)5-yl)-cyclohexanecarboxylic acid benzylamide 4683-(9-Chloro-3-methyl-4-oxo- Prep 43 3-(aminoethyl)- MS (ion spray)5H-isoxazolo[4,3-c]quinolin- pyridine 451 (M⁺)5-yl)-cyclohexanecarboxylic acid (pyridin-3-ylmethyl)-amide 4693-(9-Chloro-3-methyl-4-oxo- Prep 43 3-(aminoethyl)- MS (ion spray)5H-isoxazolo[4,3-c]quinolin- pyridine 452 (M⁺)5-yl)-cyclohexanecarboxylic acid (pyridazin-3-ylmethyl)- amide 470N-[3-(9-Chloro-3-methyl-4-oxo- L-(+)- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- mandelic 466 (M⁺) 5-yl)-cyclohexyl]-2- acidhydroxy-2-phenylacetamide 471 N-[3-(9-Chloro-3-methyl-4-oxo- D-(−)- Ex634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin- mandelic 466 (M⁺)5-yl)-cyclohexyl]-2- acid hydroxy-2-phenylacetamide 472N-[3-(9-Chloro-3-methyl-4-oxo- phenyl- Ex 634 MS (ion spray) isomer 1 =5H-isoxazolo[4,3-c]quinolin- piperidin-1- 533 (M⁺) 15.1 mg5-yl)-cyclohexyl]-2- yl-acetic isomer 2 =phenyl-2-piperidin-1-ylacetamide acid 8.8 mg 473N-[3-(9-Chloro-3-methyl-4-oxo- d/1-2-dimethyl- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- amino-3- 507 (M⁺) 5-yl)-cyclohexyl]-2-phenyl- dimethylamiao-2-phenyl-propionamide propionic acid 474N-[3-(9-Chloro-3-methyl-4-oxo- 2-methoxy-2- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin- phenyl- 494 (M⁺) 5-yl)-cyclohexyl]-2-propionic methoxy-2-phenylpropionamide acid d) Table for Cyclizationusing KOtBu 475 2-[3-(9-Chloro-3-methyl-4-oxo- prep 5 Racemic-68%5H-isoxazolo[4,3-c]quinolin-5- yield yl)cyclohexyl]-N-(3,4,5-trimethoxyphenyl)acetamide 476 2-[3-(9-Chloro-3-methyl-4-oxo- prep 12MS(ES+) 5H-isoxazolo[4,3-c]quinolin-5- m/z = 525.8 Racemicyl)cyclopentyl]-N-(3,4,5- trimethoxypheny)acetamide 4772-[3-(9-Chloro-3-methyl-4-oxo- prep 13 MS(ES+)m/z = 525.9 Racemic5H-isoxazolo[4,3-c]quinolin- 5-yl)-cyclopentyl]-N-(3,4,5-trimethoxypheny)acetamide 478 9-Chloro-3-methyl-5-{3-[2-(4- prep 43 MS(ion spray) 456.2 (M + 1) methyl-piperidin-1-yl)-2-oxo- Racemicethyl]-cyclohexyl}-5H- isoxazolo[4,3-c]quinolin-4-one 479Cis-2-[3-(9-Chloro-3-methyl- prep 158 MS (−ES) m/z 536.9 (M − H), 597.94-oxo-5H-isoxazolo[4,5-c]- (M + OAc). quinolin-5-yl)-cyclohexyl]-N-(3,4,5-trimethoxyphenyl)-acetamide e) Table for Cyclization usingKHMDS 480 2-[(1R,3S)-3-(9-Chloro-3-methyl- prep 18 MS(ES+)m/z = 526.4-oxo-5H-isoxazolo[4,3-c]- (single quinolin-5-yl)cyclopentyl]-enantiomer) N-(3,4,5-trimethoxyphenyl)- acetamide 4812-[(1R,3S)-3-(9-Chloro-3-methyl- prep 28 MS(ES+)m/z = 436.4-oxo-5H-isoxazolo[4,3- Single c]quinolin-5-yl)cyclo- enantiomerpentyl]-N-(phenyl)acetamide 482 2-[(1R,3S)-3-(9-Chloro-3-methyl- prep 28MS(ES+)m/z = 454. 4-oxo-5H-isoxazolo[4,3- Singlec]quinolin-5-yl)cyclopentyl]- enantiomer N-(4-fluorophenyl)acetamide 4832-[(1R,3S)-3-(9-Chloro-3-methyl- prep 28 MS(ES+)m/z = 437.4-oxo-5H-isoxazolo[4,3- Single c]quinolin-5-yl)-cyclo- enantiomerpentyl]-N-(pyrid-3-yl)acetamide 484 N-{2-[3-(9-chloro-3-methyl- prep 31MS(ES+)m/z = 450 4-oxo-5H-isoxazolo[4,3,- Single c]quinolin-5-yl))cyclo-enantiomer pentyl]ethyl}benzamide 485 N-[(1S,3R)-3-(9-Chloro-3-methyl-prep 33 MS(ES+)m/z = 540. 4-oxo-5H-isoxazolo[4,3- Singlec]quinolin-5-yl)cyclopentyl- enantiomerethyl]-N-(3,4,5-trimethoxyphenyl)- acetamide 486{3-(9-Chloro-3-methyl-4-oxo- prep 36 MS(ES+)m/z = 525.85H-isoxazolo[4,3-c]quinolin- Racemic 5-ylmethyl)cyclopentyl-ethyl}-N-(3,4,5-trimethoxy-phenyl)- carboxamide 4879-Chloro-3-methyl-5H-(3-phenyl- prep 78 MS(FD): M⁺ 438.3sulfanylmethyl-cyclohexyl)-5H- m/z Racemic isoxazolo[4,3-c]-quinolin-4-one 488 9-Chloro-3-methyl-5-(3-phenyl- prep 82 MS(ES): (M +1)⁺ methane-sulfonylmethylcyclohexyl)- 485.5, 487.5 m/z5H-isoxazolo[4,3-c]quinolin- 4-one Racemic 489[3-(9-chloro-3-methyl-4-oxo- prep 84 MS(ES): (M + 1)⁺5H-isoxazolo[4,3-c]quinolin- 450.4, 542.4 m/z 5-yl)cyclohexyl]- methylbenzoate Racemic 490 9-Chloro-3-methyl-5-[3-(2-oxo- prep 89 MS(ES): [M +H]⁺ = 3-phenyl-propyl)cyclohexyl]-5H- 449.1 m/z, [M − H]⁻ =isoxazolo[4,3-c]quinolin-4- 447.1 m/z one (cis) 491[3-(9-Chloro-3-methyl-4-oxo- prep 84 MS (FIA) (m/z) 465.25H-isoxazolo[4,3-c]quinolin- [M + 1] 5-yl)-cyclohexyl]- acetic acidbenzyl ester (cis) 492 N-[3-(9-Fluoro-3-methyl-4-oxo- prep 106 MS (FIA)(m/z) 434.3 5H-isoxazolo[4,3-c]quinolin- [M + 1]5-yl)-cyclohexylmethyl]benzamide (cis) 493N-[3-(9-Chloro-4-oxo-3-phenyl- prep 107 MS (FIA) (m/z) 512.45H-isoxazolo[4,3-c]quinolin- [M + 1] 5-yl)-cyclohexyl- methyl]benzamide(cis) 494 N-[3-(9-Chloro-4-oxo-5H- prep 108 MS (ES+) (m/z) 436.2isoxazolo[4,5-c]quinolin- [M + 1] 5-yl)-cyclohexylmethyl]- benzamide(cis) 495 N[3-(6-Iodo-3-methyl-4-oxo- prep 109 MS (FIA) (m/z) 540.35H-isoxazolo[4,3-c]quinolin- [M − 1] 5-yl)-cyclohexylmethyl]- benzamide(cis) 496 N-[3-(8-Iodo-3-methyl-4-oxo- prep 110 MS (FIA) (m/z) 542.25H-isoxazolo[4,3-c]quinolin- [M + 1] 5-yl)-cyclohexylmethyl]- benzamide(cis) 497 N-[3-(7-Fluoro-3-methyl-4-oxo- prep 111 MS (FIA) (m/z) 434.35H-isoxazolo[4,3-c]quinolin- [M + 1] 5-yl)-cyclohexylmethyl]- benzamide(cis) 498 N-[3-(9-Chloro-3-hexyl-4-oxo- prep 112 MS (FIA) (m/z) 520.35H-isoxazolo[4,3-c]quinolin- [M + 1] 5-yl)-cyclohexylmethyl]- benzamide(cis) 499 Phenylmethyl 2-[3-(9-iodo-3- prep 113 MS (FIA) (m/z) 557.0methyl-4-oxo-5H-isoxazolo[4,3- [M + 1] c]quinolin-5-yl)cyclo-hexyl]acetate (cis) 500 9-Chloro-3-methyl-5-{3-[2- prep 128 MS (ES):(M + 1)⁺ (toluene-3-sulfonyl)-ethyl]- 499.2, 501.2 m/zcyclohexyl}-5H-isoxazolo [4,3-c]quinolin-4-one (cis) 5019-Chloro-3-methyl-5-{(3-phenyl- prep 131 MS (FD): M⁺ 452.4thioethyl)-cyclohexyl}-5H- m/z isoxazolo[4,3-c]- quinolin-4-one (cis)502 9-Chloro-3-methyl-5-[3-(2- prep 132 MS (ES): (M + 1)⁺phenylmethane-sulfonyl-ethyl)- 499.2, 501.2 m/z cyclohexyl]-5H-isoxazolo[4,3-c]-quinolin-4-one (cis) 503 9-Chloro-5-{3-[2-(4-fluoro- prep 138 MS(ES): (M + 1)⁺ benzene-sulfonyl)-ethyl]- 503.1, 505.1 m/zcyclohexyl}-3-methyl-5H- isoxazolo[4,3-c]quinolin-4-one (cis) 504phenylmethyl 2-((3R,1R)-3-{[3- prep 144 MS (ion spray) 465(2-chloro-6-fluorophenyl)-5- (M⁺) methylisoxazol-4-yl]carbonyl-amino}cyclohexyl)acetate (cis) 505 cis-1-(9-chloro-3-methyl-4-oxo- prep160 ESMS m/e 432 ³⁵Cl 5H-isoxazolo[4,3-c]quinolin- (M⁺ + 1);5-yl)-3-[[(1,1-dimethyl- 434 ³⁷Cl ethyloxy)carbonyl]amino]- (M⁺ + 1)cyclohexane 506 [3-(9-Chloro-3-methyl-4-oxo- prep 160 MS (ES+) m/z 446.15H-isoxazolo[4,5-c]quinolin- (M + H)⁺ 5-yl)-cyclohexylmethyl]carbainicacid t-butyl ester(trans) 507 [3-(9-Chloro-3-methyl-4-oxo- prep 160 MS(ES+) m/z 446.1 5H-isoxazolo[4,5-c]quinolin- (M + H)⁺5-yl)-cyclohexylmethyl]carbamic acid f-butyl ester(cis) 508[3-(9-Chloro-3-methyl-4-oxo- prep 162 MS (ES+) m/z 500.15H-isoxazolo[4,5-c]quinolin- (M + H)⁺ 5-yl)-cyclohexyl-methyl]carbamicacid benzyl ester (cis) 509 3-[2-(9-Chloro-3-methyl]-4- prep 167 MS(ES+) m/z 554.0 oxo-5H-isoxazolo[4,3- (M + H)⁺ c]quinolin-5-yl)-cyclo-hexyl]-N-(3,4,5-trimethoxy- phenyl)propionamide 510(1R,3S)3-(9-Chloro-3-methyl-4-oxo- prep 170 ESMS: 436 (M)⁺, 4375H-isoxazolo[4,3-c]quinolin- (M + 2)⁺ 5-yl)cyclopentane-carboxylic acidbenzylamide 511 (1R,3S)-N-[3-(9-Chloro-3-methyl- prep 179 ESMS: 436(M)⁺, 437 4-oxo-5H-isoxazolo[4,3- (M + 1)⁺ c]quinolin-5-yl)-cyclo-pentylmethyl]benzamide 512 (1S,3R)-N-[3-(9-Chloro-3-methyl- prep 179ESMS: 436 (M)+, 437 4-oxo-5H-isoxazolo[4,3- (M + 1)+c]quinolin-5-yl)-cyclo- pentylmethyl]benzamide 513(1S,3R)-N-[3-(9-Chloro-3-methyl- prep 189 ESMS: 454 (M)⁺, 4554-oxo-5H-isoxazolo[4,3- (M + 1)⁺, c]quinolin-5-yl)-cyclo- 513 (M + 59)⁻pentylmethyl]-4-fluorobenzamide 514 (1S,3R)-Biphenyl-4-carboxylic prep192 ESMS: 512 (M + 1)⁺, acid [3-(9-chloro-3-methyl-4-oxo- 570 (M + 59)⁻5H-isoxazolo[4,3-c]quinolin- 5-yl)cyclopentylmethyl]amide 515(1S,3R)-N-[3-(9-Chloro-3-methyl- prep 195 ESMS: 435 (M − 1)⁻,4-oxo-5H-isoxazolo[4,3- 495 (M + 59)⁻ c]quinolin-5-yl)-cyclo-pentylmethyl]-nicotinamide 516 (1S,3R)-Furan-2-carboxylic prep 198 ESMS:426 acid [3-(9-chloro-3-methyl-4-oxo- (M + 1)⁺,5H-isoxazolo[4,3-c]quinolin- 460 (M + 35)⁻,5-yl)-cyclopentylmethyl]amide 484(M + 59)⁻ 517(1S,3R)-N-[3-(9-Chloro-3-methyl- prep 201 ESMS: 5264-oxo-5H-isoxazolo[4,3- (M + 1)⁺, c]quinolin-5-yl)cyclo- 584 (M + 59)⁻pentylmethyl]-3,4,5- trimethoxybenzamide 518(1S,3R)-N-[3-(9-Chloro-3-methyl- prep 204 ESMS: 4664-oxo-5H-isoxazolo[4,3- (M + 1)⁺, c]quinolin-5-yl)-cyclo- 524 (M + 59)⁻pentylmethyl]carbamic acid benzyl ester 519N-[3-(9-Chloro-3-methyl-4-oxo- prep 207 ESMS: 5405H-isoxazolo[4,3-c]quinolin- (M + 1)+, 5-yl)-cyclopentyl-methyl]- 574(M + 35)-,598 2-(3,4,5-trimethoxyphenyl)- (M + 59)- acetamide 520N-[3-(9-Chloro-3-methyl-4-oxo- prep 208 ESMS: 4325H-isoxazolo[4,3-c]quinolin- (M + 1)+ 5-ylmethyl)-cyclopentyl]carbamicacid t-butyl ester 521 [3-(9-Chloro-3-methyl-4-oxo- prep 209 ESMS: 4325H-isoxazolo[4,3-c]quinolin- (M + 1)+ 5-ylmethyl)-cyclopentyl]carbamicacid t-butyl ester 522 trans-[1-(9-chloro-3-methyl- prep 22 ESMS m/e 432³⁵Cl 4-oxo-5H-isoxazolo[4,3-c]- (M⁺ + 1); quinolin-5-yl)-3-[[(1,1- 434³⁷Cl dimethylethyloxy)carbonyl]- (M⁺ + 1) amino]]-cyclohexane 523N-[3-(9-Cyano-3-methyl-4-oxo- prep 267 MS(ES+)5H-isoxazole-[4,3-c]quinolin- (m/z) 441.25-yl)-cyclohexylmethyl]-benzamide [M + 1] 524[3-(9-Cyano-3-methyl-4-oxo- prep 269 MS(ES+)5H-isoxazole-[4,3-c]quinolin- (m/z) 471.25-yl)-cyclohexylmethyl]-carbamic [M + 1] acid benzyl ester 525[3-(9-Chloro-3-methyl-4-oxo- prep 278 MS(ES+)5H-isoxazole-[4,3-c]quinolin- (m/z) 346.1 5-ylmethyl)-cyclohexyl]- [M −BOC]. carbamic acid tert-butyl ester 526 N-[3-(9-Chloro-3-diethylamino-prep 280 MS(ES+) 4-oxo-5H-isoxazole[4,3- (m/z) 507.2c]quinolin-5-yl)-cyclo- [M + 1] hexylmethyl]-benzamide 527N-[3-(9-Chloro-4-oxo-3- prep 281 MS(ES+)pyrroldin-1-yl-5H-isoxazole[4,3- (m/z) 505.1 c]quinolin-5-yl)-cyclo-[M + 1] hexylmethyl]-benzamide 528 N-[3-(9-Chloro-3-ethylamino- prep 280MS(ES+) 4-oxo-5H-isoxazole[4,3- (m/z) 479.1 c]quinolin-5-yl)-cyclo- [M +1] hexylmethyl]-benzamide 529 N-[3-(9-Chloro-3-ethylsulfanyl- prep 283MS(ES+) 4-oxo-5H-isoxazole[4,3- (m/z) 496.1 c]quinolin-5-yl)-cyclo- [M +1]. hexylmethyl]-benzamide 530 N-[3-(9-Chloro-4-oxo-3- prep 278 MS(ES+)phenylamino-5H-isoxazole[4,3- (m/z) 527.2 c]quinolin-5-yl)-cyclo-hexyl-[M + 1]. methyl]-benzamide 531 N-[3-(9-Cyano-3-methyl-4-oxo- prep 316MS(ES+) 5H-isoxazole-[4,3-c]quinolin- (m/z) 441.25-yl)-cyclohexylmethyl]-benzamide [M + 1]. 532[3-(9-Cyano-3-methyl-4-oxo- prep 318 MS(ES+)5H-isoxazole-[4,3-c]quinolin- (m/z) 471.2 5-yl)-cyclohexylmethyl]- [M +1]. carbamic acid benzyl ester 533 [3-(9-Chloro-3-methyl-4-oxo- prep 327MS(ES+) 5H-isoxazole-[4,3-c]quinolin- (m/z) 346.15-ylmethyl)-cyclohexyl]-carbamic [M − BOC]. acid tert-butyl ester 534N-[3-(9-Chloro-3-diethylamino- prep 329 MS(ES+) 4-oxo-5H-isoxazole[4,3-(m/z) 507.2 c]quinolin-5-yl)-cyclo- [M + 1]. hexylmethyl]-benzamide 535N-[3-(9-Chloro-4-oxo-3-pyrroldin- prep 330 MS(ES+)1-yl-5H-isoxazole[4,3- (m/z) 505.1 c]quinolin-5-yl)-cyclo- [M + 1].hexylmethyl]-benzamide 536 N-[3-(9-Chloro-3-ethylamino- prep 331 MS(ES+)4-oxo-5H-isoxazole[4,3- (m/z) 479.1 c]quinolin-5-yl)-cyclo- [M + 1]hexylmethyl]-benzamide 537 N-[3-(9-Chloro-3-ethylsulfanyl- prep 332MS(ES+) 4-oxo-5H-isoxazole[4,3- (m/z) 496.1 c]quinolin-5-yl)-cyclo- [M +1]. hexylmethyl]-benzamide 538 N-[3-(9-Chloro-4-oxo-3-phenyl- prep 328MS(ES+) Prep 328 was sulfanyl-5H-isoxazole[4,3- (m/z) 544.2 initiallytreated c]quinolin-5-yl)-cyclo- [M + 1]. with Na hexylmethyl]-benzamidethiophenoxide (5eq) in DMF. 539 N-[3-(9-Chloro-4-oxo-3-phenyl- prep 328MS(ES+) Prep 328 was amino-5H-isoxazole[4,3- (m/z) 527.2 initiallytreated c]quinolin-5-yl)-cyclo- [M + 1]. with aniline (20eq)hexylmethyl]-benzamide in DMF. 540 [3-(9-Chloro-3-methyl-4-oxo- Prep 333MS(ES+) 5H-isoxazolo[4,3-c]quinolin- (m/z) 346.35-ylmethyl)-cyclohexyl]-carbamic [M − BOC]. acid tert.-butyl ester 541N-{2-[3-(9-Chloro-3-methyl- Prep 33 MS(ES+) 4-oxo-5H-isoxazolo[4,3-c]-m/z = 540. quinolin-5-yl)-cyclopentyl]- Single ethyl}-3,4,5-trimethoxy-enantiomer benzamide 541a {3-[(9-chloro-3-methyl-4-oxo- Prep 337 MS(ES+)5H-isoxazolo[4,3-c]quinolin- m/z = 525.8 5-yl))methyl]cyclopentyl}-N-(3,4,5-trimethoxyphenyl)- carboxamide 542 [3-(9-Chloro-3-methyl-4-oxo-Prep 338 MS(ES+) 5H-isoxazolo[4,3-c]quinolin- m/z = 402.9.5-yl)-cycloheptyl]- acetic acid methyl ester 543N-{2-[3-(9-Chloro-3-methyl- Prep 31 MS(ES+) 4-oxo-5H-isoxazolo[4,3- m/z= 450. c]quinolin-5-yl)-cyclo- pentyl]-ethyl}-benzamide 5442-[3-(9-Chloro-3-methyl-4-oxo- Prep 337 MS(ES+)5H-isoxazolo[4,3-c]quinolin- m/z = 526. 5-yl)-cyclopentyl]-N-(3,4,5-(Single trimethoxyphenyl)-acetamide enantiomer) 545[3-(9-Chloro-3-methyl-4-oxo- Ex 405 MS (ES+) 3,4-dihydro-imidazo[4,5-(m/z) 479.3 c]quinolin-5-yl)-cyclo- [M + 1] hexylmethyl]-carbamic acidbenzyl ester f) Table for Arylation: 5469-Chloro-3-methyl-5-[3-(quinolin- Ex 619 2-chloro- MS(FIA) (m/z)2-ylaminomethyl)-cyclohexyl]-5H- quinoline 473.1 (M + 1) isoxazolo[4,3-c]quinolin-4-one 547 9-Chloro-3-methyl-5-[3-[(5- Ex 619 2-chloro-6-MS(FIA) (m/z) nitro-pyridin-2-ylamino)-methyl]- nitro- 466.1 (M − 1)cyclohexyl}-5H-isoxazolo pyridine [4,3-c]quinolin-4-one 5482-{[3-(9-Chloro-3-methyl-4- Ex 619 2-chloro-3- MS(FIA) (m/z)oxo-5H-isoxazolo[4,3- nitrile- 448.1 (M + 1) c]quinolin-5-yl)cyclohexyl-pyridine methyl]- amino}-nicotinonitrile 549 9-Chloro-3-methyl-5-{3-[(5-Ex 619 2-chloro- MS(FIA) (m/z) nitropyridin-2-ylamino)methyl]-pyrimidine 424.1 (M + 1) cyclohexyl}-5H-isoxazolo [4,3-c]quinolin-4-one550 9-Chloro-5-{3-[4-chloro- Ex 619 2,4- MS(FIA) (m/z)pyrimidin-2-ylamino)- dichloropyrimidine 458.4 (M + 1)methyl]cyclohexyl}-3-methyl-5H- isomers wereisoxazolo[4,3-c]quinolin-4-one separated and 9-Chloro-5-{3-[2-chloro-pyrimidin-4-ylamino)-methyl]- cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (racemic) 551 9-Chloro-5-{3-[(6-chloro-Ex 619 2,6-dichlorobenzo- MS(FIA) (m/z) benzothiazol-2-ylamino)methyl]-thiazole 515.2 (M + 1) cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one 552 5-[3-(Benzothiazol-2-ylamino- Ex 6192-chlorobenzothiazole MS(FIA) (m/z) methyl)-cyclohexyl}-9-chloro-3-479.1 (M + 1) methyl-5H-isoxazolo [4,3-c]quinolin-4-one 5535-[3-(Benzooxazol-2-ylamino- Ex 619 2-chlorobenzooxazole MS(FIA) (m/z)methyl)cyclohexyl}-9-chloro-3- 463.3 (M + 1) methyl-5H-isoxazolo[4,3-c]quinolin-4-one g) Table for Chiral Separation: 5542-[(1S,3R)-3-(9-chloro-3-methyl- Ex 432 Retention Time =4-oxo-5H-isoxazolo[4,3- 8.56 minutes c]quinolin-5-yl))cyclohexyl]-N-(3,4,5-trimethoxyphenyl)acetamide 555 2-[(1R,3S)-3-(9-chloro-3-methyl-Ex 432 Retention Time = 4-oxo-5H-isoxazolo[4,3- 16.08 minutesc]quinolin-5-yl))cyclohexyl]- N-(3,4,5-trimethoxyphenyl)acetamide 556N-{[(1R,3S)-3-(9-chloro-3- Ex 116 Retention Time =methyl-4-oxo(5-hydroisoxazolo[4,3- 9.232 min c]quinolin-5-yl))cyclo-hexyl]methyl}benzamide 557 N-{[(1S,3R)-3-(9-chloro-3- Ex 116 RetentionTime = methyl-4-oxo-5H-isoxazolo[4,3- 12.704 min c]quinolin-5-yl))cyclo-hexyl]methyl }benzamide 558 2-[(1R,3S)-3-(9-chloro-3-methyl- Ex 479 MS(−ES) m/z 4-oxo-5H-isoxazolo[4,5- 536.9 (M − H),c]quinolin-5-yl))cyclohexyl]- 597.9 (M + OAc)N-(3,4,5-trimethoxyphenyl)acetamide 559 2-[(1S,3R)-3-(9-chloro-3-methyl-Ex 479 MS (−ES) m/z 4-oxo-5H-isoxazolo[4,5- 536.9 (M − H),c]quinolin-5-yl))cyclohexyl]- 597.9 (M + OAc)N-(3,4,5-trimethoxyphenyl)acetamide 560 N-{[(1S,3S)-3-(9-chloro-3- Ex506 MS (+ES) m/z methyl-4-oxo-5H-isoxazolo[4,5- 446 (M + H)+,c]quinolin-5-yl))cyclohexyl]- 463(M + NH3)+,methyl}(t-butoxy)carboxamide (−ES)480 (M − H + Cl)−, 504 (M − H + OAc)-561 N-{[(1R,3R)-3-(9-chloro-3- Ex 506 MS (+ES) m/zmethyl-4-oxo-5H-isoxazolo[4,5- 446 (M + H)+,c]quinolin-5-yl))cyclohexyl]- 463 (M + NH3)+,methyl}(t-butoxy)carboxamide (−ES)480 (M − H + Cl)−, 504 (M − H + OAc)-562 N-{[(1R,3S)-3-(9-chloro-3- Ex 507 MS (+ES) m/zmethyl-4-oxo-5H-isoxazolo[4,5- 446 (M + H)+,c]quinolin-5-yl))cyclohexyl]- 463 (M + NH3)+,methyl}(t-butoxy)carboxamide (−ES)480 (M − H + Cl)−, 504 (M − H + OAc)563 N-{[(1S,3R)-3-(9-chloro-3- Ex 507 MS (+ES) m/zmethyl-4-oxo-5H-isoxazolo[4,5- 446 (M + H)+, c]quinolin-5-yl))cyclo- 463(M + NH3)+, hexyl]methyl}(t- (−ES)480 butoxy)carboxamide (M − H + Cl)−,504 (M − H + OAc)- 564 3-[(1S,2S)-2-(9-chloro-3-methyl- Ex 618 MS (+ES)553.9, 4-oxo-5H-isoxazolo[4,5- 555.9 (M + H)+c]quinolin-5-yl))cyclohexyl]- N-(3,4,5-trimethoxyphenyl)- propanamide565 3-[(2S,1R)-2-(9-chloro-3-methyl- Ex 618 MS (+ES) 553.9,4-oxo-5H-isoxazolo[4,5- 555.9 (M + H)+ c]quinolin-5-yl))cyclohexyl]-N-(3,4,5-trimethoxyphenyl)- propanamide

EXAMPLE 566(2R)-N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclo-hexylmethyl]-2-amino-3-(phenylmethoxy)propanamide

A solution of(2R)-N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}-2-[(t-butoxy)carbonylamino]-3-(phenylmethoxy)-propanamide, 80 mg (0.13mmol) in 10 mL of acetic acid saturated with hydrochloric acid wasstirred for 2 h at ambient temperature and concentrated to dryness. Theresidue was dissolved in toluene and concentrated to dryness and driedunder vacuum to yield a quantitative yield of the desired product as awhite foam. ¹H—NMR is consistent with structure. MS (ion spray) 523.2(M+).

EXAMPLE 567N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-3-aminobenzamide

To a solution containing 620 mg (1.25 mmol) of a compound from Example48 in 15 mL of THF was added 848 mg (3.75 mmol) of SnCl₂.2H₂O at roomtemperature. To the resulting suspension was added 1.0 mL ofconcentrated HCl and the reaction was stirred for 15 hours at roomtemperature. The reaction was diluted with 100 mL of ethyl acetate andwashed once with brine. The organic solution was separated, dried andconcentrated to give a white foam. This crude material was purified byflash chromatography, using ethyl acetate as the eluent. The majorfractions were combined and concentrated in vacuo to give 400 mg of awhite amorphous solid. MS(FIA) m/z=465.2.

EXAMPLE 568N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-4-aminobenzamide

The title compound was prepared from the compound from Example 110according to the conditions for the preparation of Example 567. MS(FIA)m/z=465.2.

EXAMPLE 569N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cyclohexylmethyl]-3-(4methyoxy)benzyloxybenzamide

To a suspension of 150 mg (0.581 mmol) of a compound from preparation 56in 10 mL of CH₂Cl₂ was added 2 drops of DMF, followed by the addition of51 μL (0.581 mmol) of oxalyl chloride. The reaction was stirred at roomtemperature and evolution of CO gas was noted. The reaction was stirredan additional 30 minutes at room temperature and then concentrated invacuo. The resulting acid chloride was dissolved in 10 mL of CH₂Cl₂. Ina separate flask, 250 mg (0.528 mmol) of the compound from Example 302,was suspended in 10 mL of CH₂Cl₂. To this was added 110 μL oftriethylamine and the resulting solution was added to the flaskcontaining the acid chloride, followed by the addition of an additional110 μL of triethylamine. The reaction was stirred at room temperaturefor 15 hours, diluted with 50 mL of ethyl acetate and washed twice with1N HCl, twice with 1N NaOH, dried over sodium sulfate and concentratedin vacuo to give a white amorphous solid. This material wasrecrystallized from toluene to give 190 mg of a white amorphous solid.MS(ES+) m/z=586.19.

EXAMPLE 570N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cyclohexylmethyl]-3-hydroxybenzamide

To a solution containing 50 mg (0.0853 mmol) of a compound from Example569 in 2 mL of CH₂Cl₂ was added 2 mL of TFA. The reaction was stirred atroom temperature for 18 hours and concentrated in vacuo. The resultingcrude solid was recrystallized from toluene to give a white amorphoussolid. MS(ES+) m/z=466.1.

EXAMPLE 571N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cyclohexylmethyl]-4-(4-methoxy)benzyloxybenzamide

The title compound was prepared from methyl 4-hydroiybenzoate accordingto the conditions for the preparation of Example 569. MS(ES+)m/z=586.19.

EXAMPLE 572N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cyclohexylmethyl]-4-hydroxybenzamideThe title compound was prepared from a compound of Example 571 accordingto the conditions for the preparation of Example 570. MS(ES+) m/z=466.1.EXAMPLE 573N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-benzenesulfonamide

N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]benzenethioamide(0.78 g; 1.59 mmol) was dissolved in anhydrous dimethylformamide (16mL), chilled to −20° C. for 10 min, and mixed with 0.5 M potassiumbis(trimethylsilyl)amide in toluene (7.0 mL; 3.5 mmol; 2.2 equiv). Thereaction solution was stirred 10 min at −20° C. and another 35 min atroom temperature. After quenching the reaction with 1 M HCl (50 mL), thesolution was extracted with ethyl acetate (twice). The organic layer waswashed with saturated NaCl_((aq)) (twice), then dried with Na₂SO_(4(s)),filtered, and concentrated to dryness by rotary evaporation. Theresulting white solid was purified by radial chromatography (threeconsecutive times) on a 4 mm thick silica gel rotor with a 5%tetrahydrofuran/dichloromethane (v/v) mobile phase and then twice with a50% ethyl acetate/hexanes (v/v) mobile phase. Concentration ofproduct-containing fractions produced 11 mg (2% yield) of a white solid.MS(ES) calc'd: [M+H)⁺=472.0 m/z, [M−H]⁻=470.0 m/z. Found: 471.9 m/z,470.0 m/z.

EXAMPLE 574N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]benzenesulfonamide

N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]benzenethioamide(0.41 g; 0.83 mmol) was dissolved in anhydrous dimethylformamide (8 mL),chilled to −20° C. for 10 min, and mixed with 0.5 M potassiumbis(trimethylsilyl)amide in toluene (4 mL; 1.83 mmol; 2.2 equiv). Thereaction solution was stirred 10 min at −20° C. and another 35 min atroom temperature. After quenching the reaction with 1 M HCl (50 mL), thesolution was extracted with ethyl acetate (twice). The organic layer waswashed with saturated NaCl_((aq)) (twice), then dried with Na₂SO_(4(s)),filtered, and concentrated to dryness by rotary evaporation. Theresulting white solid was purified by radial chromatography on a 4 nmthick silica gel rotor with a 40% ethyl acetate/hexanes (v/v) mobilephase. Product containing fractions were combined, concentrated andfurther purified by radial chromatography (twice) on a 2 mm thick silicagel rotor with a 50% ethyl acetate/hexanes (v/v) mobile phase.Concentration of product-containing fractions produced 53 mg (14% yield)of a white solid. MS(ES) calc'd: [M+H]⁺=472.0 m/z, [M−H]⁻=470.0 m/z.Found: 472.0 m/z, 470.2 m/z.

EXAMPLE 5754-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexanecarboxylicacid 3,4,5-trimethoxybenzylamide

The compound from preparation 72 (0.40 g, 0.00098 mol) was combined withTHF (5 mL), MeOH (2 mL), water (5 mL) and 2N NaOH (5 mL) and the mixturestirred at ambient temperature until hydrolysis was complete. Themixture was concentrated in vacuo and the residue taken up in water andcarefully acidified using aq 1N HCl. The aqueous mixture was extractedwith ethyl acetate and the combined extracts were dried over sodiumsulfate. Concentration in vacuo left the crude acid which was combinedwith 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (0.186g, 0.00097 mol), 1-hydroxy-7-azabenzotriazole (0.133 g, 0.00098 mol) and3,4,5-trimethoxybenzylamine (0.193 g, 0.00098 mol) in DMF (15 mL) andthe resulting mixture stirred overnight at ambient temperature. Themixture was concentrated in vacuo and the residue taken up in water. Theaqueous mixture was extracted with CH₂Cl₂ and the combined extractsdried over sodium sulfate and concentrated in vacuo. The resultingresidue was chromatographed over silica gel using CH₂Cl₂/THF as eluentwhich allowed for isolation of 0.120 g (40%) of the desired product as ayellowish solid. MS(ES): (M+1)⁺ 540.4 m/z.

EXAMPLE 576-5775-(3-Benzenesulfinylmethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one&5-(3-Benzenesulfonylmethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

The compound from Example 487 (0.20 g, 0.00046 mol) was dissolved inCH₂Cl₂ (30 mL) and the mixture cooled under a nitrogen atmosphere in adry ice/acetone bath. Then 3-chloroperoxybenzoic acid (50%, 0.16 g,0.00046 mol) was added and the mixture stirred for 2 h while warmingnear ambient temperature. The mixture was concentrated and the residuechromatographed over silica gel using CH₂Cl₂/MeOH as eluent whichallowed for isolation of both the sulfoxide (0.132 g, 63%). MS(ES):(M+1)⁺ 455.1, 457.3 m/z, and the sulfone (0.078 g, 36%) MS(ES): (M+1)⁺471.2 m/z.

EXAMPLE 5789-Chloro-5-[3-(2-methoxyimino-3-phenylpropyl)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

To a solution of the compound from Example 490 in denatured ethanol (6mL) was added a solution of methoxyamine hydrochloride (74.5 mg; 0.892mmol; 4 equiv) and sodium acetate (73.1 mg; 0.892 mmol; 4 equiv) inwater (1 mL). The cloudy reaction mixture became clear and colorlesswhen heated to reflux. After 1.6 h the reaction solution wasconcentrated to dryness by rotary evaporation. The resulting solid wasdissolved in dichloromethane and the organic layer was washed with water(once), washed with saturated NaCl_((aq)) (once), dried withNa₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The product was isolated as a mixture of oxime isomers byradial chromatography on a 2 mm thick silica gel rotor with a 2%acetonitrile/dichloromethane (v/v) mobile phase. A clear, colorless oil(92 mg; 86%) was obtained after concentration of the appropriatefractions. TOF-MS(ES) calc'd: [M+M]⁺=478.1897 m/z. Found: 478.1891 m/z.

EXAMPLE 5792-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl]-N4-methoxyphenylacetamide

To a 7 mL scintillation vial containing 0.10 g (0.254 mmol) of acompound from preparation 95 in 3 mL of methylene chloride was added0.086 g (0.509 mmol) p-anisidine followed by 0.10 mL of triethylamine.The reaction was shaken overnight, passed through a 2 g SCX column,eluting with methylene chloride and the racemic cis product crystallizedout of one of the fractions giving 0.054 g (44%). MS(FIA) m/z=480.1.

EXAMPLE 5802-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl]-N-2-methoxy-5-nitrophenylacetamide

The title compound was prepared from a compound of preparation 95 and2-methoxy-5-nitroaniline triethylamine in a manner similar to that ofExample 579 to yield 0.051 g (38%). MS(FIA) m/z=525.2.

EXAMPLE 5819-Chloro-3-methyl-5-[3-(2-oxo-pyrrolidin-1-ylmethylcyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

To a stirred solution of the compound of Example 105 (148 mg, 0.33 mmol)in DMF (3 mL) and THF (4 mL) was added NaH (41 mg, 1.0 mmol, 60% inmineral oil) and stirred at r.t. for 1.5 hours. The reaction mixture wasdiluted with ethyl acetate, washed (brine), dried (Na₂SO₄), filtered andconcentrated. Column chromatography (silica gel, ethyl acetate) gave 82mg, 60%. MS(FIA) (m/z) 414.2 (M+1).

EXAMPLE 582N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl-2-(3,4,5-trimethoxyphenylmethyl)]acetamide

To a stirred solution ofN-[(1S,4R)-4-(9-chloro-3-methyl-4-oxo(5-hydroisoxazolo[4,3-c]quinolin-5-yl))cyclopent-2-enyl]-2-(3,4,5-trimethoxyphenyl)-acetamide(55 mg, 0.11 mmol) in DMF (5 mL) was added Rh/C (5%) and treated with H₂and stirred at r.t. for 18 hours. The mixture was filtered. The filtratewas diluted with EtOAc, washed (brine), dried (Na₂SO₄), filtered andconcentrated. Column chromatography (silica gel, hexanes/ethyl acetate,gradient) gave the title compound 38 mg, 69%. MS(FIA) (m/z) 526.3 (M+1).

EXAMPLE 583N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl-2-(3-fluorophenylmethyl)]acetamide

To a stirred solution ofN-[(1S,4R)-4-(9-chloro-3-methyl-4-oxo(5-hydroisoxazolo[4,3-c]quinolin-5-yl))cyclopent-2-enyl]-2-(3,4,5-trimethoxyphenyl)-acetamide(49 mg, 0.11 mmol) in EtOAc (5 mL) was added Rh/C (5%, catalytic amount)and treated with H₂ and stirred at r.t. for 18 hours. The mixture wasfiltered. The filtrate was diluted with EtOAc, washed (brine), dried(Na₂SO₄), filtered and concentrated. Column chromatography (silica gel,hexanes/ethyl acetate, gradient) gave the title compound 48 mg, 97%.MS(FIA) (m/z) 454.1 (M+1).

EXAMPLE 584 and 5853-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)cyclohexane-carboxylicacid (3,4,5-trimethoxyphenyl)

A compound from preparation 101 (0.2 g, 0.54 mmol), 1 N NaOH (1.32 ml,1.32 mmol), and MeOH (8 ml) were heated at 50° C. for 2 h. The reactionwas cooled to r.t., acidified to pH<3, and concentrated using benzene toazeotrope. The residue, EDCI (0.2 g, 1.07 mmol), 3,4,5-trimethoxyaniline(0.119 g, 0.65 mmol), DMAP (0.013 g, 0.11 mmol), and dichloromethane(5.5 ml) were mixed under N₂. The mixture was diluted with EtOAc,washed, dried, filtered, and concentrated to give 585 (0.05 g, 17%) and584 (0.07 g, 24%) after radial chromatography (silica gel, 5%acetone/dichloromethane). 585: MS(FIA) (m/z) 540.4 [M+1]. 584: MS(FIA)(m/z) 540.4 [M+1].

EXAMPLE 5863-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)cyclohexane-carboxylicAcid (2-methoxy-5-nitrophenyl)

In a fashion similar to that described for Example 585, methyl3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanecarboxylate (0.2 g, 0.54 mmol), 1 N NaOH (1.32 ml, 1.32 mmol), MeOH (8ml), EDCI (0.2 g, 1.07 mmol), 2-methoxy-5-nitroaniline (0.11 g, 0.65mmol), DMAP (0.013 g, 0.11 mmol), dichloromethane (5.5 ml) gave b (0.052g, 18%) and a (0.068 g, 24%) after radial chromatography (silica gel, 2%acetone/dichloromethane).

b: MS(FIA) (m/z) 523.1 [M−1].

a: MS(FIA) (m/z) 523.1 [M−1].

EXAMPLE 5879-Chloro-5-[3-(4,4-dimethyl-4,5-dihydro-oxazol-2-ylmethyl)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4one

The compound from preparation 43 (0.2 g, 0.54 mmol) was dissolved indichloromethane (3.6 ml) followed by addition of oxalyl chloride (0.108ml, 1.08 mmol) and DMF (0.005 ml). After 1 h of stirring, the volatileswere removed. The residue was dissolved in dichloromethane (1.5 ml) and2-amino-2-methyl-1-propanol (0.1 ml, 1.08 mmol) was added. The reactionwas stirred for 3 h then concentrated. The reaction was dissolved inthionyl chloride (2 ml) and stirred for 40 min. The reaction wasconcentrated, added 0.1 N NaOH, and extracted with EtOAc (3×). Thecombined organic layers were washed (brine), dried (MgSO₄), filtered,and concentrated. Column chromatography (silica gel, hexanes/EtOAcgradient) gave the title compound (0.06 g, 26%). MS(FIA) (m/z) 428.2[M+1].

EXAMPLE 588 & 5895-(3-Benzooxazol-2-ylmethyl-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]-quinolin-4-one&2-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-N-(2-hydroxyphenyl)acetamide

In a fashion similar to that described for Example 587, compound frompreparation 43 (0.159 g, 0.423 mmol), oxalyl chloride (0.073 ml, 0.84mmol), dichloromethane (2.8 ml), DMF (0.005 ml), 2-aminophenol (0.2 g,1.07 mmol), dichloromethane (1.5 ml), and thionyl chloride (2 ml) gavethe title compounds5-(3-benzooxazol-2-ylmethyl-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one,588, (0.089 g, 47%) and2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-N-(2-hydroxy-phenyl)-acetamide,589, (0.031 g, 16%) after column chromatography (silica gel,acetone/dichloromethane gradient).

588: MS(FIA) (m/z) 448.1 [M+1]. 589: MS(FIA) (m/z) 466.2 [M+1].

EXAMPLE 5909-Chloro-3-methyl-5-[3-(4-phenyl-4,5-dihydro-oxazol-2-ylmethyl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

In a fashion similar to that described for Example 587, a compound frompreparation 43 (0.159 g, 0.423 mmol), oxalyl chloride (0.073 ml, 0.84mmol), dichloromethane (2.8 ml), DMF (0.005 ml), R-(−)-2-phenylglycinol(0.115 g, 0.84 mmol), dichloromethane (1.5 ml), and thionyl chloride (2ml) gave the title compound (0.105 g, 52%) after column chromatography(silica gel, acetone/dichloromethane gradient). MS(FIA) (m/z) 476.1[M+1].

EXAMPLE 5919-Chloro-3-methyl-5-[3-(4-phenyl-4,5-dihydro-oxazol-2-ylmethyl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

In a fashion similar to that described for Example 587, compound frompreparation 43 (0.159 g, 0.423 mmol), oxalyl chloride (0.073 ml, 0.84mmol), dichloromethane (2.8 ml), DMF (0.005 ml), S-(+)-2-phenylglycinol(0.115 g, 0.84 mmol), dichloromethane (1.5 ml), and thionyl chloride (2ml) gave the title compound (0.07 g, 35%) after column chromatography(silica gel, acetone/dichloromethane gradient). MS(FIA) (m/z) 476.1[M+1].

EXAMPLE 5925-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-4,5-dihydroisoxazolo[4,3-c]-quinoline-8-carboxylicAcid Methyl Ester

To a mixture of Example 496 (0.034 g, 0.063 mmol), acetonitrile (8 ml),MeOH (3 ml), Et₃N (0.15 ml, 0.2 mmol) submerged in a 65° C. oil bath wasadded PdCl₂(dppf) (0.003 g, 0.003 mmol) under CO atmosphere (balloon).The reaction was stirred for 5 h. The reaction was cooled to roomtemperature and concentrated. The residue was diluted with EtOAc, washed(H₂O then brine), dried (MgSO₄), filtered, and concentrated. Columnchromatography (silica gel, acetone/dichloromethane gradient) gave thetitle compound (0.021 g, 70%).

MS(ES+) (m/z) 474.2 [M+1].

EXAMPLE 5935-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-4,5-dihydroisoxazolo[4,3-c]-quinoline-6-carboxylicAcid Methyl Ester

In a fashion similar to that described for Example 592,N-[3-(6-Iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-benzamide(0.048 g, 0.089 mmol), acetonitrile (10 ml), MeOH (5 ml), Et₃N (0.04 ml,0.267 mmol), and PdCl₂(dppf) (0.004 g, 0.004 mmol) gave the titlecompound (0.035 g, 83%) after column chromatography (silica gel,acetone/dichloromethane gradient). MS(FIA) (m/z) 472.3 [M−1].

EXAMPLE 594[3-(9-Iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-5-yl)cyclohexylmethyl]-carbamicAcid t-butyl Ester

To a solution of phenylmethyl2-[(1R,3S)-3-(9-iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]acetate(1 g, 2.14 mmol) and t-BuOH (15 ml) submerged in a 50° C. oil bath wasadded Et₃N (0.386 ml, 2.78 mmol) and DPPA (0.6 ml, 2.78 mmol) under N₂.This solution was heated at reflux overnight. The solvents were removedin vacuum and the residue was chromatographed (silica gel, EtOAc/hexanesgradient) to give the title compound (0.47 g, 40%). MS(FIA) (m/z) 538.3[M+1], 438.0 [M−BOC].

EXAMPLE 595N-[3-(3-Methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]benzamide

To a mixture of Example 106 (0.07 g, 0.129 mmol) andtetrakis(triphenyl-phosphine)palladium (0.015 g, 0.0129 mmol) in toluene(1.3 ml) under N₂ was added tributyltin hydride (0.042 ml, 0.155 mmol)and heated at 80° C. for 17 h. Added more tributyltin hydride (0.069 ml,0.258 mmol) to the mixture and heated at this temperature for 24 h. Thereaction was cooled to room temperature, applied to a silica gel column,and elution (acetone/dichloromethane gradient) gave the title compound(0.02 g, 38%).

MS(BS+) (m/z) 416.2 [M+1].

EXAMPLE 596N-{3-[9-(4-Methoxyphenyl)-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamide

To a mixture of Example 106 (0.1 g, 0.185 mmol),tetrakis(triphenyl-phosphine)palladium (0.043 g, 0.037 mmol), and4-methoxyphenylboronic acid (0.7 g, 0.46 mmol) in dioxane (2 ml) underN2 was added Na2CO3(aq) (0.185 ml, 0.37 mmol) and heated at reflux for72 h. The reaction was cooled to room temperature, diluted with EtOAc,washed (H2O then brine), dried (MgSO4), filtered, and concentrated.Radial chromatography (silica gel, 33.3% EtOAc/hexanes) gave the titlecompound (0.057 g, 59%). MS(FIA) (m/z) 522.2 [M+1].

EXAMPLE 5975-[3-(Benzoylamino-methyl)-cyclohexyl]-3-methyl-4-oxo-5-hydro-isoxazolo[4,3-c]quinoline-9-carboxylicAcid Methyl Ester

In a fashion similar to that described for Example 272, a compound fromExample 106 (0.88 g, 1.63 mmol), acetonitrile (60 ml), MeOH (20 ml),Et₃N (0.68 ml, 4.89 mmol), and PdCl₂(dppf) (0.066 g, 0.08 mmol) gave thetitle compound (0.687 g, 89%) after column chromatography (silica gel,acetone/dichloromethane gradient).

MS(FIA) (m/z) 474.1 [M+1].

EXAMPLE 5985-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicAcid

A compound from Example 597 (0.35 g, 0.74 mmol), 5.0 N NaOH (2.4 ml,11.84 mmol), and dioxane (7 ml) were allowed to react for 3 h at 90° C.in a fashion similar to that of Example 472, give the title compound(0.28 g, 85%). MS(ES+) (m/z) 460.2 [M+1].

EXAMPLE 5995-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicAcid Amide

To a solution of Example 598, (0.05 g, 0.11 mmol), EDCI (0.032 g, 0.165mmol), and HOBt (0.023 g, 0.165 mmol) in DMF (1.5 ml) under N₂ was addedNH₄Cl (0.009 g, 0.165 mmol) and diisopropylamine (0.046 ml, 0.33 mmol).The reaction was stirred overnight. The mixture was diluted with EtOAc,washed (1.0 N HCl saturated with NaCl), dried (MgSO₄), filtered, andconcentrated. Column chromatography (silica gel, hexanes/EtOAc gradient)gave the title compound (0.024 g, 48%). MS(ES+) (m/z) 459.1 [M+1].

EXAMPLE 6005-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicAcid diethylamide

In a fashion similar to that described for Example 596, a compound fromExample 598 (0.05 g, 0.11 mmol), EDCI (0.032 g, 0.165 mmol), HOBt (0.023g, 0.165 mmol), DMF (1.5 ml), and diethylamine (0.017 ml, 0.165 mmol)gave the title compound (0.039 g, 68%) after column chromatography(silica gel, acetone/dichloromethane gradient).

MS(ES+) (m/z) 515.2 [M+1].

EXAMPLE 6015-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicAcid Ethyl Ester

To a solution of Example 598, (0.05 g, 0.11 mmol) in DMF (1 ml) under N₂was added iodoethane (0.062 ml, 0.33 mmol) and Cs₂CO₃ (0.036 g, 0.11mmol). The mixture was stirred overnight, diluted with EtOAc, washed(H₂O then brine), dried (MgSO₄), filtered, and concentrated. Columnchromatography (silica gel, acetone/dichloromethane gradient) gave thetitle compound (0.043 g, 80%). MS(FIA) (m/z) 488.4 [M+1].

EXAMPLE 6025-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicAcid Benzyl Ester

In a fashion similar to that described for Example 601, a compound fromExample 598 (0.05 g, 0.11 mmol), benzyl bromide (0.039 ml, 0.33 mmol),Cs₂CO₃ (0.036 g, 0.11 mmol), and DMF (1 ml) gave the title compound(0.051 g, 85%) after column chromatography (silica gel,acetone/dichloromethane gradient). MS(FIA) (m/z) 548.3 [M-1].

EXAMPLE 6035-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicAcid Ethoxycarbonylmethyl Ester

In a fashion similar to that described for Example 601, a compound fromExample 598 (0.05 g, 0.11 mmol), ethyl bromoacetate (0.036 ml, 0.33mmol), Cs₂CO₃ (0.036 g, 0.11 mmol), and DMF (1 ml) gave the titlecompound (0.054 g, 90%) after column chromatography (silica gel,acetone/dichloromethane gradient). MS(FIA) (m/z) 546.2 [M+1].

EXAMPLE 6045-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicAcid Isopropyl Ester

In a fashion similar to that described for Example 601, a compound fromExample 598 (0.05 g, 0.11 mmol), 2-iodopropane (0.033 ml, 0.33 mmol),Cs₂CO₃ (0.036 g, 0.11 mmol), and DMF (1 ml) gave the title compound(0.021 g, 38%) after column chromatography (silica gel,acetone/dichloromethane gradient). MS(ES+) (m/z) 502.2 [M+1].

EXAMPLE 6055-[3-(Benzoylamino-methyl)-cyclohexyl]-3-methyl-4oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicAcid Ethylamide

In a fashion similar to that described for Example 599, a compound fromExample 598 (0.05 g, 0.11 mmol), EDCI (0.032 g, 0.165 mmol), HOBt (0.023g, 0.165 mmol), DMF (1.5 ml), ethylamine (0.55 ml, 1.1 mmol), anddiisopropylethylamine (0.06 ml, 0.33 mmol) gave the title compound(0.003 g, 6%) after column chromatography (silica gel,acetone/dichloromethane gradient).

MS(ES+) (m/z) 487.3 [M+1].

EXAMPLE 6065-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicAcid Methyl Amide

To a solution of Example 598 (0.05 g, 0.11 mmol) in toluene (1.5 ml)under N₂ was added thionyl chloride (0.5 ml) and heated at reflux for 3h. The solution was concentrated using toluene to azeotrope. The residuewas dissolved in dichloromethane (2 ml) under N₂ and added methylamine(0.55 ml, 1.1 mmol) and DMAP (0.025 g, 0.22 mmol). The reaction wasstirred overnight, diluted with dichloromethane, washed (0.1 N HCl, H₂O,and brine), dried (MgSO₄), filtered, and concentrated. Columnchromatography (silica gel, acetone/CH₂Cl₂ gradient) gave the titlecompound (0.029 g, 56%). MS(ES+) (m/z) 473.2 [M+1].

EXAMPLE 607N-{3-[9-(4,5-Dihydro-oxazol-2-yl)-3-methyl{3oxo-H-isoxazolo[4,3-c]quinolin-5-yl]-cyclohexylmethyl}benzamide

To a solution of Example 598 (0.1 g, 0.22 mmol) in toluene (4 ml) underN₂ was added thionyl chloride (1 ml) and heated at reflux for 3 h. Thesolution was concentrated using toluene to azeotrope and the residue wasdissolved in dichloromethane (4 ml) under N₂. Ethanolamine (0.131 ml,2.2 mmol) and DMAP were added to the reaction and stirred overnight. Themixture was diluted with dichloromethane, washed (5% NaHCO₃, H₂O, andbrine), dried (MgSO₄), filtered, and concentrated. The residue wasdissolved in thionyl chloride (2 ml), stirred overnight, andconcentrated. The crude material was purified by column chromatography(silica gel, acetone/CH₂Cl₂ gradient) to give the title compound (0.01g, 10%). MS(ES+) (m/z) 485.2 [M+1], 521.2 [M+HCl].

EXAMPLE 608N-[3-(9-Hydroxymethyl-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamide

To a solution of Example 598 (0.01 g, 0.022 mmol) in toluene (0.4 ml)under N₂ was added thionyl chloride (0.1 ml) and heated at reflux for 3h. The solution was concentrated using toluene to azeotrope and theresidue was dissolved in dichloromethane (0.5 ml). To this solution wasadded NaBH₄ (0.008 g, 0.22 mmol) in THF (0.5 ml) and stirred overnight.The mixture was diluted with MeOH (1 ml) and EtOAc, washed (0.1 N NaOH,H₂O, and brine), dried (MgSO₄), filtered, and concentrated to give thetitle compound (0.005 g, 53%) without further purification.

MS(ES+) (m/z) 446.2 [M+1].

EXAMPLE 609N-[3-(3-Methyl-4-oxo-9-propionyl-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamide

To a solution of Example 598 (0.05 g, 0.011 mmol) in toluene (2 ml)under N₂ was added thionyl chloride (1 ml) and heated at reflux for 3 h.The solution was concentrated using toluene to azeotrope. To a solutionof diethylzinc (1 ml, 1 mmol) under N₂ stirring at −20° C. was added asolution of CuCN (0.093 g, 1.04 mmol) and LiCl (0.086 g, 2.02 mmol) inTHF (1.5 ml). This mixture was gradually allowed to warm to 0° C.,stirred for 15 min at this temperature, and cooled to −25° C. To thissolution was added the acid chloride residue in THF (0.5 ml) and stirredfor 1.5 h gradually allowing to warm to 0° C. The reaction was dilutedwith NH4Cl_((aq)) and extracted with dichloromethane (2×). The combinedorganic layers were washed (brine), dried (MgSO₄), filtered, andconcentrated. Column chromatography (silica gel, acetone/dichloromethanegradient) gave the title compound (0.013 g, 28%).

MS(ES+) (m/z) 472.2 [M+1].

EXAMPLE 610 & 6115-[3-(2-Benzenesulfinyl-ethyl)-cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4one&5-[3-(2-Benzenesulfonyl-ethyl)-cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

A compound from Example 501 (0.20 g, 0.00044 mol) was dissolved inCH₂Cl₂ (30 mL) and the mixture cooled under a nitrogen atmosphere in anice bath. Then 3-chloroperoxy-benzoic acid (50%, 0.15 g, 0.00044 mol)was added and the mixture stirred for 6 h while warming to ambienttemperature. The mixture was quenched with aq NaHCO₃ and extracted withCH₂Cl₂. The combined extracts were dried over sodium sulfate andconcentrated in vacuo. The resulting residue was chromatographed oversilica gel using CH₂Cl₂/THF as eluent which allowed for isolation ofboth the pure sulfoxide (0.075 g, 36%), MS(ES): (M+1)⁺ 469.1, 471.2 m/z,and pure sulfone (0.025 g, 12%). MS(ES): (M+1)⁺ 485.4, 487.3 m/z.

EXAMPLE 6125-(3-Aminomethyl-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one(d,l)

To 41.5 mg (0.093 mmol) of Example 507 was added 0.75 ml trifluoroaceticacid. After 10 min stirring at rt, starting material (via TLC) wasconsumed. The crude reaction mixture was diluted with EtOAc and sat'daq. bicarbonate and transferred to a sep funnel. The aqueous phase wasreextracted two add'l times with EtOAc, and the combined organics werewashed with brine, dried over Na₂SO₄, filtered and concentrated toafford clean amine (28 mg, 87%) which was used without furtherpurification. MS (+ES) m/z 345.9 (M+H)+.

EXAMPLE 613(1R,3S)-5-(3-Aminomethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[^(4,5)-c]quinolin-4-one

The product from Example 562 (0.069 g, 0.16 mmol) was treated with TFA(2 mL) and stirred at room temperature for 15 min. The reaction wasadded dropwise to sat HCO₃ ⁻ (10 mL) and the product was extracted withCH₂Cl₂ (5×10 mL). The solvent was removed in vacuo to afford 0.05 g(94%) of the title compound as a white solid. MS (ES+) m/z 346.0 (M+H)⁺.

EXAMPLE 614(1S,3R)-5-(3-Aminomethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

The product of Example 553 (0.08 g, 0.18 mmol) was treated with TFA (2mL) and stirred at room temperature for 20 min. The reaction was addeddropwise to sat HCO₃ ⁻ (10 mL) and the product was extracted with CH₂Cl₂(5×10 mL). The solvent was removed in vacuo to afford 0.047 g (76%) oftitle compound as a white solid. MS (ES+) m/z 346.0 (M+H)⁺.

EXAMPLE 615(1R,3S)-5-(3-Aminomethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

A solution of the product from Example 508 (0.40 g, 0.83 mmol) in dryCH₂Cl₂ (5 mL) was treated with iodotrimethylsilane (0.25 g, 1.25 mmol)and stirred at r.t. After 3 hr the reaction was quenched with MeOH (2mL) and stirred for an additional 30 min. The solution was thenconcentrated to an orange solid and taken up in EtOAc (20 mL) and 1 NHCl (20 mL) and transferred to a sep funnel. The organic layer wasextracted and the aqueous layer was washed with additional EtOAc (2×10mL). The pH of the aqueous layer was then adjusted to ph˜12 with 5 MNaOH. The product was extracted with EtOAc (3×25 mL). The EtOAcextractions were dried over sodium sulfate, filtered, and the solventremoved in vacuo to afford 0.240 g (84%) as a white solid which was usedwithout further purification. MS (ES+) m/z 346.0 (M+H)⁺.

EXAMPLE 6165-(3-Aminomethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

The product from Example 560 (30 mg, 0.067 mmol) was treated withHCl-1.0 M in HOAc (2 mL). The reaction was stirred at r.t. for 20minutes. Acetonitrile (2 mL) was added and the solution was concentratedto a white solid. The white solid was suspended in ether and filtered toafford 15 mg (70%) as a white solid. MS (ES+) m/z 346.0 (M+H)⁺.

EXAMPLE 6175-(3-Aminomethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

The product of Example 561 (30 mg, 0.067 mmol) was treated with HCl-1.0M in HOAc (2 mL). The reaction was stirred at r.t. for 20 minutes.Acetonitrile (2 mL) was added and the solution was concentrated to awhite solid. The white solid was suspended in ether and filtered toafford 13 mg (60%) as a white solid. MS (MS+) m/z 346.0 (M+H)⁺.

EXAMPLE 6183-[2-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexyl]-N-(3,4,5-trimethoxyphenyl)propionamide

The amide from preparation 165 (24 mg, 0.042 mmol) was dissolved inanhydrous DMF (0.5 ml). NaHMDS (1 M in THF, 0.046 ml, 1.1 eq) was addeddropwise. After 1 hr, sm still present, and additional base (1.1 eq) wasadded, followed by a third volume (1.1 eq) an hour later. The reactionwas then allowed to proceed o.n. The reaction was then quenched with 0.1N HCl and EtOAc, transferred to a sep funnel, and the aqueous phase wasreextracted two additional times. the combined organics were washed withsat'd bicarbonate, then with brine, dried over Na₂SO₄, filtered andconcentrated to afford 21 mg of crude product. Purification over silica(1 g Bond-Elut cartridge, 2:1 EtOAc/hexanes) afforded 21 mg of product(40%).

MS (+Es) 553.9, 555.9 (M+H)⁺.

EXAMPLE 6195-(3-Aminomethylcyclopentyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one

A mixture of Example 518 (240 mg, 0.5 mmol) and trimethyl silyl iodide(154, 077 mmol) dissolved in methylene chloride (10 mL) was stirredovernight at rt. The reaction mixture was passed through Bond Elut SCXcolumn (20 cc, 5 g), eluted with ammonia solution in methanol (1M, 20mL) and evaporated to obtain the title compound (150 mg, 90%). ESMS: 332(M+1)⁺.

EXAMPLE 6205-[((1R,3S)-3-Aminocyclopentyl)methyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

N-{(1S,3R)-3-[(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))methyl]cyclopentyl}(tert-butoxy)carboxamidewas converted to the amine by TFA in DCM at rt. for three hours. ESMS:332 (M+1)+.

EXAMPLE 6215-[((1S,3R)-3-Aminocyclopentyl)methyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one

N-{(1R,3S)-3-[(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin-5-yl))methyl]cyclopentyl}(tert-butoxy)carboxamidewas converted to the amine as described in Example 620. ESMS: 332(M+1)+.

EXAMPLE 622cis-1-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-(3-phenyluriedo)-cyclohexane

To the suspension ofcis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-amino-cyclohexane(0.0446 g, 0.121 mmol) in 1 mL anhydrous THF at RT was added 2N NaOH(0.60 mL, 0.121 mmol). After 5 min. the phenylisocyanate (0.013 mL,0.121mmol). After 20 min. the reaction was diluted with EtOAc, washed withwater and concentrated to near dryness. After sonication and filtrationa white solid (0.0412, 75%) was obtained. ESIMS m/e 451 ³⁵Cl (M⁺+1) and453 ³⁷Cl (M⁺+1).

EXAMPLE 623cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-[3-(phenylmethyl)-uriedo]cyclohexane

A procedure similar to that for Example 622 was used to prepare thetitle compound as a yellow solid (0.110 g, 87%). ESIMS m/e 465 ³⁵Cl(M⁺+1) and 467 ³⁷Cl (M⁺+1).

EXAMPLE 624cis-1-(9-chloro-3-methyl-4-oxo5H-isoxazolo[4,3-c]quinolin-5-yl)-3-(3-cyclohexyluriedo)Cyclohexane

A procedure similar to that for Example 622 was used to prepare thetitle compound as a yellow solid (0.106 g, 86%). ESIMS m/e 457 ³⁵Cl(M⁺+1) and 459 ³⁷Cl (M⁺+1).

EXAMPLE 625 Preparation of racemiccis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-(3-ethyluriedo)Cyclohexane

A procedure similar to that for Example 622 was used to prepare thetitle compound as a yellow solid (0.102 g, 94%). ESIMS m/e 403 ³⁵Cl(M⁺+1) and 405 ³⁷Cl (M⁺+1).

EXAMPLE 626cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-(3-propyluriedo)cyclohexane

A procedure similar to that for Example 622 was used to prepare thetitle compound as a yellow solid (0.106 g, 94%). ESIMS m/e 417 ³⁵Cl(M⁺+1) and 419 ³⁷Cl (M⁺+1).

EXAMPLE 627(1S,3R)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-[((2S)-2-amino-2-phenylacetyl)amino]cyclohexaneHydrochloride

To the product from Example 11 (0.015 g, 0.027 mmol) in 1 mL CH₂Cl₂ wasadded 1 mL 4M HCl in dioxane. After 3 h the mixture was stipped todryness to give the title compound as a white solid (0.0131 g, 98%).ESIMS m/e 465 ³⁵Cl (M⁺+1) and 467 ³⁷Cl (M⁺+1).

EXAMPLE 628(1R,3S)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-[((2S)-2-amino-2-phenylacetyl)amino]cyclohexaneHydrochloride

To the product from Example 11 (0.013 g, 0.023 mmol) in 1 mL CH₂Cl₂ wasadded 1 mL 4M HCl in dioxane. After 3 h the mixture was stipped todryness to give, a white solid (0.0115 g, 100%). ESIMS m/e 465 ³⁵Cl(M⁺+1) and 467 ³⁷Cl (M⁺+1).

EXAMPLE 629(1S,3R)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-[((2R)-2-amino-2-phenylacetyl)amino]cyclohexane Hydrochloride

To the product from Example 11 (0.013 g, 0.019 mmol) in 1 mL CH₂Cl₂ wasadded 1 mL 4M HCl in dioxane. After 3 h the mixture was stipped todryness to give a white solid (0.0098 g, 100%). ESIMS m/e 465 ³⁵Cl(M⁺+1) and 467 ³⁷Cl (M⁺+1).

EXAMPLE 630 AND 631N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-(5-methyltetrazol-2-yl)-2-phenylacetamide&N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-(5-methyltetrazol-1-yl)-2-phenylacetamide

To a 0° C. solution ofN-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-hydroxy-2-phenyl(30 mg, 0.06 mmol) in toluene (4 mL) was added triphenylphosphine (20mg, 0.08 mmol), 5-methyltetrazole (8 mg, 0.10 mmol), anddiethylazodicarboxylate (16 μL, 0.10 mmol) dropwise. After 30 minutesthe reaction was allowed to warm to room temperature overnight.Purification gave 4.4 mg and 10.2 mg, respectively as white solids, 43%combined yield. ¹H NMR: consistent with structures. MS (ion spray) 532(M⁺).

EXAMPLE 6325-(3-Aminomethyleyclohexyl)-9-chloro-3-methyl-5H-isoxaolo[4,3-c]quinolin-4-oneHydroiodide

To a 0° C. solution of[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-carbamicacid be (5.0 g, 10.4 mmol) in dichloromethane (100 mL) was addediodotrimethylsilane (3.6 mL, 25.0 mmol) dropwise, and the solutionallowed to warm to room temperature overnight. Methanol (6.1 mL, 150.0mmol) was added dropwise over two minutes, and the reaction stirred for30 minutes. The reaction was concentrated and suspended in ethyl ether.After 15 minutes of sonication, the solids were removed by filtrationand washed with ethyl ether. The tan powder was dried on a vacuum pumpto give 4.61 g as the 1.2 HI salt, 89% yield. ¹H NMR: consistent withstructure. MS (ion spray) 346 (M⁺).

EXAMPLE 6332-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-phenylacetamide

A compound from Example 235 (180 mg, 0.32 mmol) was combined withtrifluoroacetic acid (0.75 mL) in dichloromethane (4.0 mL) and themixture stirred at ambient temperature until deprotection was complete.The mixture was then concentrated in vacuo and the residue treated withaqueous NaHCO₃ and extracted with ethyl acetate. Concentration left aresidue, which was chromatographed over silica(methanol/dichloro-methane) allowing for isolation of the desiredproduct (145 mg, 97%) as a white solid. MS(ES): (M+1)⁺ 465.2, 467.2 m/z.

EXAMPLE 6345-(3-Aminocyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-oneHydroiodide

To a solution of[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]carbamicacid methyl ester, 2.0 g (5.1 mmol) in 50 mL of dichloromethane wasadded 1.74 mL (12.2 mmol) of trimethylsilyliodide. The reaction mixturewas stirred overnight at ambient temperature and was quenched dropwisewith 3.0 mL (73.4 mmol) of methanol. The mixture was stirred 30 minutesat ambient temperature and was concentrated to dryness. The residue wastriturated with ether, filtered and dried to provide a quantitativeyield of the desired isomer as a tan solid. ¹H—NMR is consistent withstructure. MS (ion spray) 332.1 (M+ for free base).

EXAMPLE 635 Pyridazine-4-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]amide

4-Methylpyridazine, 4.0 mL (44.6 mmol) was dissolved in 200 mL of waterand 16.2 g (103 mmol) of potassium permanganate was added. The resultingslurry was refluxed for 30 min, then an additional 8.5 g (54 mmol) ofpotassium permanganate was added. The resulting slurry was refluxed for24 h, then filtered hot through celite. The resulting solution waswashed with ether, acidified to pH=7 with 5 N HCl, and concentrated to avolume of 80 mL. This solution was acidified to pH=2 with 1 N HCl andextracted with ethyl acetate and with 20% isopropanol/chloroform. Thecombined organics were dried over sodium sulfate, filtered andconcentrated to dryness to yield 320 mg of a tan foam. 1H NMR indicateda 2:1 mixture of 4-pyridazine carboxylic acid: starting material4-methylpyridazine.

This mixture, 40 mg, was added to a solution of 66 mg (0.14 mmol) of acompound from Example 632 in 5 mL of N,N-dimethylformamide. To thissolution was added 23 mg (0.17 mmol) of 1-hydroxy-7-azabenzotriazole, 33mg (0.17 mmol) of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimidehydrochloride, 5 mg of 4-dimethylaminopyridine and 60 μL (0.42 mmol) oftriethylamine. Yield=33 mg (53%) of the desired isomer as a white foam.¹H—NMR is consistent with structure. MS (ion spray) 452.2 (M+).

EXAMPLE 636 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]amideHydrochloride

A solution of3-(9-Chloro-3-methyl-4oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester, 74 mg (0.125 mmol) in 5 mL of acetic acidsaturated with HCl gas was stirred for three hours at ambienttemperature, then was concentrated to dryness. The residue was slurried3× in toluene and concentrated to dryness to give a quantitative yieldof the desired isomer as a white solid. ¹H—NMR is consistent withstructure. MS (ion spray) 491.0 (M+).

EXAMPLE 637 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid[3-(9chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amideHydrochloride

A solution of3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl[-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester, 74 mg (0.125 mmol) in 5 mL of acetic acidsaturated with HCl gas was stirred for four hours at ambienttemperature, then was concentrated to dryness. The residue was slurried3× in toluene and concentrated to dryness to give a quantitative yieldof the desired isomer as a white solid. ¹H—NMR is consistent withstructure. MS (ion spray) 491.3 (M+).

EXAMPLE 6382-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-phenylacetamide

{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methyl}-carbamicacid tert-butyl ester (1.24 g; 2.2 mmol) was dissolved in excess, neatacetic acid saturated with HCl_((g)) (20 mL). After stirring 30 min atroom temperature, the solution was concentrated to dryness by rotaryevaporation. Acetic acid was removed from the resulting solid byconsecutive dissolution in, and drying from, acetonitrile (thrice) andthen diethyl ether (once). The solid was dissolved in 25% (v/v)isopropyl alcohol in chloroform, washed with saturated NaHCO_(3(aq)),and dried by rotary evaporation to yield the desired product in 97%isolated yield.

MS(ES) calc'd: [M+H]⁺=465.2 m/z. Found: 465.2 m/z.

EXAMPLE 6392-Amino-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenylmethyl}-2-methylpropionamideHydrochloride

A compound from Example 321 was deprotected in a manner similar toExample 638 and kept as the hydrochloride salt. MS(ES) calc'd:[M+H]⁺=550.2 m/z; [M−H⁻=548.2 m/z; [M+Cl]⁻=584.2 m/z. Found: 550.0 m/z;548.0 m/z; 584.0 m/z.

EXAMPLE 6402-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-pyridin-3-ylacetamide

A compound from Example 326 was deprotected in a manner similar toExample 638. The free base was separated into individual diastereomersby radial chromatography on a 2 mm thick silica gel rotor with a 2%methanol/dichloromethane (v/v) mobile phase (300 mL) followed byincreasing methanol to 10% in step gradients (each mobile phase nowcontaining 1% triethylamine). The desired product was isolated as 13 mgof isomer 1, 18 mg of isomer 2, and 7 mg mixed product.

Isomer 1 MS(ES) exact mass calc'd: [M+H]⁺=466.1646 m/z. Found: 466.1648m/z.

Isomer 2 MS(ES) exact mass calc'd: [M+H]⁺=466.1646 m/z. Found: 466.1663m/z.

EXAMPLE 641N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexylmethyl]-thiobenzamide

A solution ofcis-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl))cyclohexyl]methyl}benzamide(0.1 g, 0.2 mmol) in pyridine (10 mL) was treated with P₂S₅ (0.37 g, 1.7mmol) and heated to reflux. The reaction was stirred for 1 hour atreflux and then allowed to cool to r.t. The reaction was quenched withwater (150 mL) A white precipitate formed and was filtered to afford alight yellow solid. This solid was taken up in CH₂Cl₂ (15 mL) andpurified by silica gel column chromatography. The product was elutedwith 1% MeOH in CH₂Cl₂. The solvent was removed to afford 0.082 g (81%)of a yellow solid. MS m/z (ES+) 465.8 (M+H)⁺, (ES−) 463.8 (M−H)⁻.

EXAMPLE 642N-[3-(9-Chloro-3-methyl-4-oxo-2,4-dihydropyrazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamide

Cis-N-({3-[3-(aminoethylidene)-5-chloro-2,4-dioxohydroquinolyl]-cyclohexyl}methyl)benzamide(0.15 g, 0.3 mmol) and hydrazine hydrate-85% (0.016 g, 0.49 mmol) inEtOH (20 mL). The reaction was heated to reflux and stirred for 6 hr.The reaction was then concentrated to a solid and taken up in CH₂Cl₂.This solution was purified by silica gel column chromatography using 50%EtOAc in CH₂Cl₂ to elute the product. The solvent was removed to afford0.095 g (64%) as a yellow solid. MS (ES+) m/z 448.9 (M+H)⁺, (ES−) m/z446.9 (M−H)⁻, 506.9 (M+CH3COO⁻)⁻.

EXAMPLE 643N-[3-(9-Chloro-3-methyl-4-oxo-2,4-dihydropyrazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-6-fluoronicotinamide

cis-N-({3-[3-(Aminoethylidene)-5-chloro-2,4-dioxohydroquinolyl]-cyclohexy}methyl)(6-fluoro(3-pyridyl))carboxamide(0.92 g, 0.2 mmol) and hydrazine hydrate-85% (0.063 g, 0.3 mmol) in EtOH(20 mL). The reaction was heated to reflux and stirred for 1 hr. Thereaction was then concentrated to a solid and taken up in CHCl₃. Thissolution was purified by silica gel column chromatography using 5% MeOHin CHCl₃ to elute the product. The solvent was removed to afford 0.02 g(22%) as a white solid. MS (ES+) m/z 468.1 (M+H)⁺, (ES−) m/z 466.1(M−H)⁻, 526.2 (M+CH3COO⁻)⁻.

EXAMPLE 644[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexylmethyl]-carbamicAcid Benzyl Ester

A solution ofN-{[3-(3-acetyl-4-amino-5-chloro-2-oxohydroquinolyl)-cyclohexyl]-methyl}(phenylmethoxy)carboxamide(0.02 g, 0.04 mmol) in acetic acid (2 mL) was treated with hydroxylaminehydrochloride (3 mg, 0.046 mmol). The solution was heated to reflux andstirred 4 hr. The reaction was then diluted in CH₂Cl₂ (50 mL) and washedwith 5M NaOH (3×10 mL) and brine (2×10 mL). The organic was dried oversodium sulfate and the solvent removed. The crude product was purifiedby silica gel column chromatography using 10% EtOAc in CH₂Cl₂ to elutethe product. The solvent was removed in vacuo to afford 0.014 g (70%) ofthe title compound as an off-white solid.

MS (ES+) m/z 500.1 (M+H)⁺.

EXAMPLE 645N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexylmethyl]-6-fluoronicotinamide

A solution ofN-{[3-(3-acetyl-4-amino-5-chloro-2-oxohydroquinolyl)cyclohexyl]-methyl}(6-fluoro(3-pyridyl))carboxamide(0.035 g, 0.07 mmol) in acetic acid (5 mL) was treated withhydroxylamine hydrochloride (7.8 mg, 0.11 mmol). The solution was heatedto reflux and stirred 3 hr. The reaction was then diluted in CHCl₃ (50mL) and washed with sat'd sodium bicarbonate (3×10 mL) and brine (2×10mL). The organic was dried over sodium sulfate and the solvent removed.The crude product was purified by silica gel column chromatography using50% EtOAc in CHCl₃ to elute the product. The solvent was removed invacuo to afford 0.025 g (72%) of the title compound as a white solid. MSm/z (ES+) 468.8 (M+H)⁺, (ES−) 466.8 (M−H)⁻, 526.8 (M+CH3COO⁻)⁻.

EXAMPLE 646N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-4-fluoro-benzamide

To a solution of a compound from Example 524 (0.106 g, 0.23 mmol) inCH₂Cl₂ (10 ml) under N₂ was added TMSI (0.36 ml, 2.52 mmol) and stirredovernight. Added MeOH (5 ml) and stirred for 1 h to quench the reaction.The mixture was concentrated, triturated with toluene and dried toobtain a crude solid. This was mixed with 4-fluorobenoyl chloride (0.093ml, 0.8 mmol)in CH₂Cl₂ (5 ml)under N₂ and triethylamine (0.22 ml, 1.6mmol) was added dropwise. After stirring overnight, the mixture wasdiluted with CH₂Cl₂, washed (0.1N HCl then brine), dried (MgSO₄),filtered, and concentrated. Flash chromatography (silica gel,acetone/CH₂Cl₂ gradient) gave the title compound (0.085 g, 88%). MassSpectrum (ES+) (m/z) 459.1 [M+1].

EXAMPLE 647N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)cyclohexylmethyl]-3,4-difluorobenzamide

In a fashion similar to that described for Example 527, a compound fromExample 524 (0.106 g, 0.23 mmol), CH₂Cl₂ (10 ml), TMSI (0.36 ml, 2.52mmol), 3,4-difluorobenzoyl chloride (0.093 ml, 0.8 mmol), CH₂Cl₂ (5 ml),and triethyamine (0.22 ml, 1.6 mmol) gave the title compound (0.087 g,87%) after flash chromatography (silica gel, acetone/CH₂Cl₂ gradient).Mass Spectrum (ES+) (m/z) 477.1 [M+1].

EXAMPLE 648N-[3-(9-Chloro-4-oxo-3-phenylsulfanyl-5H-isoxazole[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamide

To a solution ofN-{[3-(3-acetyl-4-amino-5-chloro-2-oxohydroquinolyl)-cyclohexyl]methyl}(6-fluoro(3-pyridyl))carboxamide(0.1 g, 0.2 mmol) in DMF (2.5 ml) under N₂ was added sodiumthiophenoxide (0.132 g, 1.0 mmol) and stirred for 2 h. The reaction wasdiluted with EtOAc, washed (H₂O then brine), dried (MgSO₄), filtered,and concentrated. The residue was dissolved in DMF (2 ml) under N₂,cooled to 0 degrees C., and KHMDS (0.566 ml, 0.28 mmol) was added over15 min. After 30 min, the solution was diluted with EtOAc, washed (H20and brine), dried (MgSO₄), filtered, and concentrated. Flashchromatography (silica gel, Acetone/CH₂Cl₂ gradient) gave the titlecompound (0.045 g, 41%). Mass Spectrum (ES+) (m/z) 544.2 [M+1].

EXAMPLE 649N-[3-(9-Chloro-3-ethoxy4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)cyclohexylmethyl]-benzamide

To a solution of 278 (0.1 g, 0.2 mmol) in DMF (2.5 ml) under N₂ wasadded sodium ethoxide (0.33 ml at 21% wt., 1.0 mmol) and stirred for 2h. The reaction was diluted with EtOAc, washed (H₂O then brine), dried(MgSO₄), filtered, and concentrated. Purification by flashchromatography gave the title compound (0.025 g, 26%) (silica gel,acetone/CH₂Cl₂ gradient). Mass Spectrum (ES+) (m/z) 480.2 [M+1].

EXAMPLE 650N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-methylamino-acetamideHydrochloride

A solution of the compound from Example 333, 66 mg (0.13 mmol) in 10 mLof HCl-saturated acetic acid was stirred 4 hours at rt., thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness to give a quantitative yield of the desiredisomer as a white foam. ¹H—NMR is consistent with structure. MS (ionspray) 403.2 (M+).

EXAMPLE 6512-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-methyl-propionamideHydrochloride

A solution of the compound from Example 335, 64 mg (0.12 mmol) in 10 mLof HCl-saturated acetic acid was stirred 3 hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to give a quantitative yield of the desiredisomer as a white foam. MS (ion spray) 417.1 (M+).

EXAMPLE 6522-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-acetamideHydrochloride

A solution of the compound from Example 336,49 mg (0.10 mmol) in 10 mLof HCl-saturated acetic acid was stirred 3 hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to give a quantitative yield of the desiredisomer as a tan foam. MS (ion spray) 389.1 (M+).

EXAMPLE 653N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-phenyl-2-piperazin-1-ylacetamideDihydrochloride

A solution of the compound from Example 339, 171 mg (0.27 mmol) in 10 mLof HCl-saturated acetic acid was stirred 2 hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to give a quantitative yield of the desiredmixture of isomers as a tan foam. ¹H—NMR is consistent with structure.MS (ion spray) 389.1 (M+). The isomers were separated by chiralchromatography in a similar fashion to that described for Example 554 toyield 31.5 mg (19%) of isomer 1 as a white foam and 32.9 mg (20%) ofisomer 2 as a white foam. I.S. (534.2) M+.

EXAMPLE 654N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-methylamino-2-phenylacetamideHydrochloride

A solution of the compound from Example 340, 130 mg (0.22 mmol) in 10 mLof HCl-saturated acetic acid was stirred 2 hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to give a quantitative yield of the desiredmixture of isomers as a white foam. MS (ion spray) 479.2 (M+).

EXAMPLE 655 1-Aminocyclohexanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]amideHydrochloride

A solution of the compound from preparation 229a, 198 mg (0.35 mmol) in15 mL of HCl-saturated acetic acid was stirred three hours at rt. thenconcentrated to dryness. The residue was slurried 3× in acetonitrile andconcentrated to dryness to give 160 mg (93%) of the desired isomer as awhite solid. MS (ion spray) 457.2 (M+1).

EXAMPLE 6562-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-cyclohexylacetamideHydrochloride

A solution of the compound from Example 355, 80 mg (0.14 mmol) in 30 mLof HCl-saturated acetic acid was stirred four hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness to give 60 mg (85%) of the desired isomer as atan solid. MS (ion spray) 471.2 (M+).

EXAMPLE 6572-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-cyclohexylacetamideHydrochloride

A solution of the compound from Example 356, 100 mg (0.17 mmol) in 30 mLof HCl-saturated acetic acid was stirred four hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness to give 47 mg (55%) of the desired isomer as atan solid. ¹H—NMR is consistent with structure. MS (ion spray) 471.2(M+).

EXAMPLE 658 2-Aminoindan-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]amideHydrochloride

A solution of a compound from Example 634, 220 mg (0.37 mmol) in 40 mLof HCl-saturated acetic acid was stirred three hours at rt., thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness give a quantitative yield of the desired isomeras a white solid. MS (ion spray) 491.2 (M+).

EXAMPLE 6592-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3c]quinolin-5-yl)cyclohexyl]-3-phenylpropionamide

A solution of the compound from Example 370, 84 mg (0.14 mmol) in 10 mLof HCl-saturated acetic acid was stirred four hours at rt., thenconcentrated to dryness. The residue was slurried 3× in acetonitrile andconcentrated to dryness give a quantitative yield of the desired isomeras a tan foam. MS (ion spray) 479.1 (M+).

EXAMPLE 6605-(3-Amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one

A compound from Example 634 (350 mg,0.95 mmol) was treated with excessaqueous NaHCO₃ and the mixture extracted with EtOAc. The combinedextracts were dried over Na₂SO₄ and concentrated in vacuo to yield 309mg (98%) of the title compound.

EXAMPLE 661N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)cyclohexylmethyl]-4-fluorobenzamide

To a solution of a compound from Example 532 (0.106 g, 0.23 mmol) inCH₂Cl₂ (2 mL) under N₂ was added TMSI (0.046 mL, 0.32 mmol) and stirredovernight. Added MeOH (1 mL) and stirred for 1 h to quench the reaction.The mixture was concentrated, triturated with toluene and dried toobtain a crude solid. This was mixed with 4-fluorobenoyl chloride (0.093mL, 0.8 mmol) in CH₂Cl₂ (5 mL) under N₂ and Et₃N (0.22 mL, 1.6 mmol) wasadded dropwise. After stirring overnight, the mixture was diluted withCH₂Cl₂, washed (0.1N HCl then brine), dried (MgSO₄), filtered, andconcentrated. Flash chromatography (silica gel, Acetone/CH2C12 gradient)gave the title compound (0.085 g, 88%). Mass Spectrum (ES+) (m/z) 459.1[M+1].

EXAMPLE 662N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)cyclohexylmethyl]-3,4-difluorobenzamide

In a fashion similar to that described for Example 542, a compound fromExample 413 (0.1 g, 0.21 mmol), CH₂Cl₂ (2 mL), TMSI (0.046 mL, 0.32mmol), 3,4-difluorobenoyl chloride (0.093 mL, 0.8 mmol), CH₂Cl₂ (5 mL),and Et₃N (0.22 mL, 1.6 mmol) gave the title compound (0.087 g, 87%)after flash chromatography (silica gel, acetone/CH₂Cl₂ gradient). MassSpectrum (ES+) (m/z) 477.1 [M+1].

EXAMPLE 663N-[3-(9-Chloro-3-ethoxy-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)cyclohexylmethyl]-benzamide

To a solution of a compound from preparation 328 (0.1 g, 0.2 mmol) inDMF (2.5 mL) under N₂ was added sodium ethoxide (0.33 mL at 21% wt., 1.0mmol) and stirred for 2 h. The reaction was diluted with EtOAc, washed(H₂O then brine), dried (MgSO₄), filtered, and concentrated.Purification by flash chromatography gave the title compound (0.025 g,26%) (silica gel, acetone/CH₂Cl₂ gradient). Mass Spectrum (ES+) (m/z)480.2 [M+1].

EXAMPLE 664N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-6-fluoronicotinamide

To a solution ofN-{[3-(9-cyano-3-methyl-4-oxo(5-hydroisoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}(phenylmethoxy)carboxamide(0.27 g, 0.58 mmol) in CH₂Cl₂ (7 mL) under N₂ was added TMSI (0.2 mL,1.4 mmol) and stirred overnight. Added MeOH (3 mL) and stirred for 1 hto quench the reaction. The mixture was concentrated, triturated withtoluene and dried to obtain a crude solid. This was mixed with6-fluoronicontic acid (0.114 g, 0.81 mmol) in DMF (5 mL) under N₂ and tothis solution was added EDCI (0.16 g, 0.81 mmol) and DMAP (0.131 g, 1.08mmol). After stirring overnight, the mixture was diluted with EtOAc,washed (H₂O then brine), dried (MgSO₄), filtered, and concentrated.Flash chromatography (silica gel, Acetone/CH₂Cl₂ gradient) gave thetitle compound (0.198 g, 80%). Mass Spectrum (ES+) (m/z) 460.3 [M+1].

EXAMPLE 6656-Chloro-N-[3-(9-cyano-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]nicotinamide

In a fashion similar to that described for Example 664, a compound fromExample 532 (0.1 g, 0.21 mmol), CH₂Cl₂ (2 mL), TMSI (0.046 mL, 0.32mmol), 6-chloronicotinic acid (0.068 g, 0.43 mmol), DMF (4 mL), EDCI(0.62 g, 0.32 mmol) and DMAP (0.052 g, 0.43 mmol) gave the titlecompound (0.045 g, 44%) after flash chromatography (silica gel,EtOAc/Hexanes gradient). Mass Spectrum (ES+) (m/z) 476.2 [M+1].

EXAMPLE 666N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-6-methylnicotinamide

In a fashion similar to that described for Example 664, a compound fromExample 532 (0.1 g, 0.21 mmol), CH₂Cl₂ (2 mL), TMSI (0.046 mL, 0.32mmol), 6-methyl-nicotinic acid (0.059 g, 0.43 mmol), DMP (4 mL), EDCI(0.62 g, 0.32 mmol) and DMAP (0.131 g, 1.08 mmol) gave the titlecompound (0.045 g, 44%) after flash chromatography (silica gel,EtOAc/Hexanes gradient). Mass Spectrum (ES+) (m/z) 456.2 [M+1].

EXAMPLE 667N-[3-(9-Amino-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-benzamide

To a solution of a compound from preparation 333 (0.24 g, 0.42 mmol) inTHF (4.2 mL) under N₂ was added TBAF (0.84 mL, 0.84 mmol, 1.0M in THF)dropwise and stirred for 4 h. The reaction was applied directly to asilica gel column and eluted with EtOAc which gave the title compound(0.18 g, 99%). Mass Spectrum (ES−) (m/z) 429.3 [M−1]

EXAMPLES 668 & 6699-Chloro-5-[3-(2-hydroxy-2-phenylethylamino)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one&9-Chloro-5-[3-(2-hydroxy-1-phenylethylamino)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

To a stirred solution of a compound from Example 634 (440 mg, 1.33 mmol)in abs. EtOH (60 mL) was added S-styrene oxide (159.2 mg, 1.33 mmole)under N₂ atmosphere. The reaction mixture was refluxed for 22 h. Thesolvent was removed on Buchi and the crude was chromatographed byElution solution systems (40L column, NH₃ in MeOH: EtOAc, gradient). Thetitle compounds were yielded (A, 201 mg; B, 41 mg, 40.3% yield). MassSpectrum(FIA); A(m/z) 452.2 (M+1); B(m/z) 452.2 (M+1).

EXAMPLES 670 & 6719-Chloro-5-[3-(2-hydroxy-2-phenylethylamino)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one&9-Chloro-5-[3-(2-hydroxy-1-phenylethylamino)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one

To a stirred solution of a compound from Example 634 (441 mg, 1.33mmole) in abs. EtOH (60 mL) was added R-styrene oxide (160 mg, 1.33mmole) under N₂ atmosphere. The reaction mixture was refluxed for 202 h.The solvent was removed on Buchi and the crude was chromatographed byElution solution systems (40L column, NH₃ in MeOH: EtOAc, gradient). Thetitle compounds were yielded (A, 161 mg; B. 40 mg, 33.4% yield). MassSpectrum (FIA) A(m/z) 452.2 (M+1); B(m/z) 452.2 (M+1).

EXAMPLE 6729-Chloro-3-methyl-5-[3-(2-oxo-5-phenyloxazolidin-3-yl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

To a stirred solution of a compound from Example 668 (41 mg, 0.091mmole) in THF (2 mL) was added DCC (15 mg, 0.091 mmole) and Et₃N (0.013mL, 0.091 mmole). The reaction mixture was stirred at rt. under N₂atmosphere for 18 h. It was diluted with EtOAc, washed with brine, driedover Na₂SO₄ and concentrated. The resulted crude oil was chromatographed(gradient, hexanes: EtOAc) and the desired product was yielded as whitefoam solid (23 g, 54%). Mass Spectrum: m/z calcd. 478.1533, Found478.1544

EXAMPLE 6739-Chloro-3-methyl-5-[3-(2-oxo-5-phenyloxazolidin-3-yl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

To a stirred solution of a compound from Example 670 (50 mg, 0.11 mmol)in THF (2 mL) was added DCC (18 mg, 0.11 mmol), Et₃N (0.016 mL, 0.11mmol) and DMAP (catalytic amount). The reaction mixture was stirred atrt. under N₂ atmosphere for 48 h. It was diluted with EtOAc, washed withbrine, dried over Na₂SO₄ and concentrated. The resulted crude oil waschromatographed (gradient, hexanes: EtOAc) and the desired product wasyielded as white foam solid (21 g, 40%). Mass Spectrum: m/z calcd.478.1533, Found 478.1565.

EXAMPLE 6749-Chloro-3-methyl-5-[3-(2-oxo-4-phenyloxazolidin-3-yl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

To a stirred solution of a compound from Example 669 (97 mg, 0.21 mmole)in THF (4 mL) was added DCC (34.1 mg, 0.21 mmole), Et₃N (0.03 mL, 0.21mmole) and DMAP (catalytic amount). The reaction mixture was stirred atrt. under N₂ atmosphere for 18 h. It was diluted with EtOAc, washed withbrine, dried over Na₂SO₄ and concentrated. The resulted crude oil waschromatographed (gradient, hexanes: EtOAc) and the desired product wasyielded as white foam solid (40 g, 40%). Mass Spectrum(FIA)(m/z) 478.1(M+1).

EXAMPLE 6759-Chloro-3-methyl-5-[3-(2-oxo-4phenyloxazolidin-3-yl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

To a stirred solution of a compound from Example 671 (64 mg, 0.14 mmole)in CH₂Cl₂ (5 mL) was added DCC (115 mg, 0.7 mmole), Et₃N (0.02 mL, 0.14mmole) and DMAP (catalytic amount). The reaction mixture was stirred atrt. under N₂ atmosphere for 48 h. It was diluted with CH₂Cl₂, washedwith brine, dried over Na₂SO₄ and concentrated. The resulted crude oilwas chromatographed (gradient, hexanes: EtOAc) and the desired productwas yielded as white foam solid (51 g, 76%). Mass Spectrum (FIA) (m/z)478.0 (M+1).

EXAMPLE 6769-Chloro-5-{3-[2-(6-chloropyridin-3-yl)-2-hydroxyethylamino]cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin4one

To a stirred solution of 6-chloronicotinic acid (900 mg, 5.7 mmol) inTHF (7 mL) was added BH₃ (16 mL, 17.1 mmol, 1M in THF) under N₂atmosphere. The reaction mixture was stirred for 5 h. It was quenchedwith methanol (5 mL) and then concentrated. The crude was dissolved inEtOAc (30 mL), washed with 1N NaOH (15 mL×3), brine, dried andconcentrated. Yield: 615 mg (75%) of 6-chloro-pyridin-3-yl-methanol. Tothis alcohol (615 mg, 4.28 mmol) solution in CH₂Cl₂ (8 mL) was addedDess-Martin reagent (5.4 mg, 12.8 mmol). It was stirred at rt. for 2 hand then diluted with CH₂Cl₂. The resulting solution was washed withNaOH (1N, 2×5 mL), brine, dried and concentrated. 516 mg (85%) of yellowsolid as the desired 6-chloro-pyridine-3-carbaldehyde. To a solution ofabove aldehyde (401 mg, 2.82 mmol) in CH₂Cl₂ (10 mL) was added 50% NaOHsolution (9.3 mL), trimethylsulfonium iodide (1.15 g, 5.64 mmol) andtetrabutylammonium iodide (11 mg). It was refluxed for 48 h and pouredonto ice water. The organic layer was extracted with CH₂Cl₂, washed withbrine, dried and concentrated. The crude epoxide was chromatographed(gradient, hexanes: EtOAc) and 190 mg (43%) yellow oil was yielded asdesired 2-Chloro-5-oxiranyl-pyridine. To the solution of2-chloro-5-oxiranyl-pyridine (118.4 mg, 0.76 mmol) in absolute ethanol(40 mL) was added a compound from Example 660 (252 mg, 0.76 mmol). Thereaction mixture was refluxed for 24 h and concentrated.

EXAMPLE 677[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cycloheptylmethyl]-carbamicAcid 2-trimethylsilanylethyl Ester

To a warm solution of 0.2 g (0.52 mmol) of a compound from Example 680in toluene (4 mL) was added 0.154 mL (0.72 mmol) of DPPA followed by 0.1mL (0.72 mmol) of Et₃N. After heating the solution at 80° C. for 2hours, 0.11 mL (0.78 mmol) of the silyl alcohol was added and thereaction was heated at 85° C. for 12 hours. The reaction was cooled,diluted with EtOAc, rinsed with water followed by brine, and dried overNa₂SO₄. The solvent was removed in vacuo and the residue waschromatographed on silica gel with 2/1 hexanes/EtOAc to yield 0.127 g ofthe title compound.

MS(ES+)m/z=504.

EXAMPLE 678N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)R-cycloheptylmethyl]benzamide

A solution of 0.052 g (0.2 mmol) of a compound from Example 677 in THF(6 mL), and 4.5 mL of TBAF (1.OM in THF)(4.5 mmol) was heated at 60° C.for 4 hours. The solution was cooled to ambient temperature and water (2mL) then 0.028 g of anhydrous K₂CO₃ (0.2 mmol) were added followed by0.016 g (0.11 mmol) of benzoyl chloride. The reaction was stirred 12hours, after which the THF was replaced with EtOAc and rinsed with 1NHCl and dried over Na₂SO₄. The organic layer was concentrated in vacuoto a residue, which was chromatographed on silica gel with 2/1hexanes/EtOAc to yield 0.011 g of the title compound.

MS(ES+)m/z=464.

EXAMPLE 679 N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo [4,3-c]quinolin-5-yl)-R-cycloheptylmethyl]-4-fluorobenzamide

In a manner similar to the preparation of Example 678, 0.052 g (0.1mmol) of a compound from Example 678 yielded 0.012 g of the titlecompound.

MS(ES+)m/z=482.

EXAMPLE 680[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cycloheptyl]aceticAcid

A suspension of 0.82 g (2.0 mmol) of a compound from Example 424 in 1NNaOH (45 mL) and MeOH (125 mL) was stirred for 16 hrs. at ambienttemperature. The MeOH was removed in vacuo and the reaction was cooledand neutralized with 3N HCl. The acidic aqueous layer was extracted withEtOAc, rinsed with water and concentrated in vacuo at 40° C. to yield0.78 g of the title compound.

MS ES+)m/z=388.9.

EXAMPLE 681[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cycloheptylmethyl]-carbamicAcid Methyl Ester

In a manner similar to the preparation of Example 677 (except theintermediate isocyanate was trapped with MeOH instead of TMS ethanol)0.68 g (1.8 mmols) of a compound from Example 680 was converted to 0.43g of the title compound.

MS(ES+)m/z=418.1.

EXAMPLE 682N-[3R-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)R-cycloheptylmethyl]benzamide

A suspension of 0.036 g (0.1 mmol) of a compound from Example 632, 0.028g (2.0 mmol) of anhydrous K₂CO₃, and 0.013 mL (1.1 mmol) of benzoylchloride in 3 mL of THF/H₂O 2/1 was stirred 15 hours. The solvent wasremoved in vacuo and the residue was taken into EtOAc and rinsed withNaHCO₃ sat., 1N HCl, and brine. The organic layer was dried over anhyd.Na₂SO₄ and the solvent was removed in vacuo. The residue wascrystallized from MeOH to yield 0.28 g of the title compound.

MS(ES+)m/z=464.1.

EXAMPLE 6832-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-3-phenylpropionamide

A solution of{1-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-phenyl-ethyl}-carbamicacid tert-butyl ester, 82 mg (0.14 mmol) in 15 mL of HCl-saturatedacetic acid was stirred three hours at rt., then concentrated todryness. The residue was slurried 3× in acetonitrile and concentrated todryness to give a quantitative yield of the title compound as a tanfoam. MS (ion spray) 479.2. (M+).

EXAMPLE 6842-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-3-hydroxypropionamide

A solution of{1-[3-(9-Chloro-3-methyl-4-oxo5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-hydroxy-ethyl}-carbamicacid tert-butyl ester, 73 mg (0.14 mmol) in 8 mL of 25% TFA in CH₂Cl₂was stirred rt. for three hours then concentrated to dryness. Theresidue was partitioned between 20% isopropanol/chloroform and saturatedaqueous NaHCO₃. The organics were washed with saturated NaHCO₃, washedwith brine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by radial chromatography using MeOH/chloroform aseluent and concentrated to dryness to yield 40 mg (69%) of the titlecompound as a white solid. ¹H—NMR is consistent with structure. MS (IS)419.1 (M+).

EXAMPLE 6852-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-3-hydroxypropionamide

A solution of{1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-hydroxy-ethyl}-carbamic acid tert-butyl ester, 92.3 mg (0.18 mmol) in 8 mL of 25% TFAin CH₂Cl₂ was stirred rt. for three hours then concentrated to dryness.The residue was partitioned between 20% isopropanol/chloroform andsaturated aqueous NaHCO₃. The organics were washed with saturatedNaHCO₃, washed with brine, dried over Na2SO4, filtered and concentratedto dryness. The residue was purified by radial chromatography usingMeOH/chloroform as eluent and concentrated to dryness to yield 37 mg(50%) of the title compound as a white solid. MS (IS) 419.2 (M+).

EXAMPLE 686N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-6-dimethylaminonicotinamide

A solution of compound from Example 245, 50 mg, (0.10 mmol) in 2.0 mL(4.0 mmol) of 2N N,N-dimethylamine in THF was stirred 24 H in a sealedtube at 90° C. then concentrated to dryness. The residue was dissolvedin 20% isopropanol/chloroform and washed with saturated aqueous sodiumbicarbonate, washed with brine, dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by radialchromatography using a methanol/chloroform gradient as eluent and wasconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to yield 48 mg (96%) of the desired isomer as awhite foam.

¹H—NMR is consistent with structure.

MS (ion spray) 494.2 (M+).

EXAMPLE 687N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-6-methylaminonicotinamide

A solution of a compound from Example 245, 50 mg, (0.10 mmol) in 2.0 mL(4.0 mmol) of 2N methylamine in tetrahydrofuran was stirred 24 H in asealed tube at 100° C. then concentrated to dryness. Some mechanicalloss occurred. The residue was dissolved in 20% isopropanol/chloroformand washed with saturated aqueous sodium bicarbonate, washed with brine,dried over sodium sulfate, filtered and concentrated to dryness. Theresidue was purified by radial chromatography using amethanol/chloroform gradient as eluent and was concentrated to dryness.The residue was slurried in ether/hexanes and concentrated to dryness toyield 30 mg (62%) of the desired isomer as a white foam. MS (ion spray)480.1 (M+).

EXAMPLE 688N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-(pyridin-3-yloxy)propionamide(Isomers 1 & 2)

The isomers ofN-[3-(9-Chloro-3-methyl-4oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-3-yloxy)-propionamide(mixture of isomers, 142 mg (0.29 mmol) was separated via chiralchromatography to yield 63.5 mg of crude isomer 1 and 60.2 mg of crudeisomer 2. Isomer 1 was purified by radial chromatography(methanol/chloroform gradient) and concentrated to dryness to yield 55.7mg (39%) of the desired isomer as a tan foam. 1H—NMR is consistent withstructure.

MS (ion spray) 481.2 M+.

Isomer 2 was purified by radial chromatography (methanol/chloroformgradient) and concentrated to dryness to yield 51.3 mg (36%) of thedesired isomer as a white foam.

¹H—NMR is consistent with structure.

MS (ion spray) 481.2 M+.

EXAMPLE 689N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl]methyl}benzamide

In the same manner as preparation 17,N-(t-butoxycarbonyl)2-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentylamine(0.06 g, 0.14 mmol) of was deprotected to yield 0.044 g (0.133 mmol) ofthe free amine MS(ES+)m/z=332, which was dissolved in dichloromethane(2.5 mL). To the solution was added 0.0222 mL (0.16 mmol) of Et₃Nfollowed by 0.019 mL (0.16 mmol) of benzoyl chloride. After 45 min, thesolvent was removed in vacuo, replaced with ethyl acetate and theorganic layer was rinsed with 1N HCl followed by 1N NaOH, then water.The organic layer was dried and the solvent was removed in vacuo to givea residue which was chromatographed on silica gel with ethylacetate/hexane 1:1 to yield 0.035 g of the title compound.MS(ES+)m/z436. Cis (racemic)

EXAMPLE 690 Phenylmethyl2-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]acetate

To a solution of phenylmethyl2-((1R,3S)-3-{[4-(2-chloro-6-fluorophenyl)-2-methyl(3-furyl)]carbonylamino}cyclohexyl)acetate,5.71 g (11.8 mmol) in 100 mL of N,N-dimethylformamide at ambienttemperature was added 47 mL (23.6 mmol) of 0.5 M potassiumbis(trimethylsilyl)amide in toluene dropwise. After 10 min., thereaction was quenched with saturated ammonium chloride and extractedwith ethyl acetate. The combined organics were washed with brine, driedover sodium sulfate, filtered and concentrated to dryness. The residuewas chromatographed on silica gel using ethyl acetate/hexanes as eluentto yield 3.8 g (70%) of the desired product as a green oil.

¹H—NMR is consistent with structure.

MS (ion spray) 465.2 (M+1).

EXAMPLE 691 5-{(1S,3S)-3-[2-(phenylamino)ethyl]cyclohexyl}-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

N-{(1S,3S)-3-[2-(phenylamino)ethyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide (54 mg;0.118 mmol) was dissolved in anhydrous DMF (2 mL) under a dry nitrogenatmosphere at room temperature. When potassium bis(trimethylsilyl)amide(0.5 M in toluene; 572 μL; 2.2 equiv) was added dropwise to thissolution, a clear orange color formed. After 5 min, the reaction waschilled in an ice bath, quenched with 1N HCl_((aq)) (10 mL), andextracted with ethyl acetate (twice). The organic layer was washed withsaturated NaCl_((aq)) (once), dried with Na₂SO_(4(s)), filtered, andconcentrated to dryness by rotary evaporation. The product was purifiedby radial chromatography on a 2 mm thick silica gel rotor. Adichloromethane mobile phase was ineffective at purifying the product.Re-chromatography with a 100% hexanes mobile phase followed by a 20%ethyl acetate/hexanes (v/v) mobile phase separated product fromimpurities. After drying from diethyl ether, an off-white foam (43 mg;84%) was obtained.

TOF-MS(ES) calc'd: [M+H]⁺=436.1792 m/z. Found: 436.1797 m/z.

EXAMPLE 6925-[3-(2-Aza-bicyclo[2.2.1]hept-5-en-2-ylmethyl)-cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

To a suspension of a compound from preparation 48 (500 mg, 1.0 mmol) inwater (5 mL) was added formaldehyde (0.24 mL, 3.0 mmol) dropwise, andthe mixture stirred rapidly under nitrogen. After 5 minutes, freshlycracked cyclopentadiene (0.41 mL, 5.0 mmol) was added dropwise. Thesolution was stirred under nitrogen at rt. overnight. The solution wasdiluted with a saturated aqueous sodium bicarbonate solution, extractedwith dichloromethane (×3), and the organics dried over magnesium sulfateand concentrated. Purification by flash chromatography on silica gel(eluting with 1-4% methanol/chloroform/0.5% NH₄OH) gave 183.7 mg of thetitle compound as a white foam, 43% yield. MS (ion spray) 424 (M⁺).

EXAMPLE 693 1-Amino-cyclopentanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-4H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amideHydrochloride

A compound from Example 460 (89.9 mg, 0.17 mmol) was dissolved inHCl_((g))/AcOH (5 mL, ˜3N) and stirred at rt. After 1 h, additionalHCl_((g))/AcOH (5 mL, ˜3N) was added. After 5 h, the mixture wasconcentrated, followed by azeotropic removal of water with acetonitrilein vacuo (×3). To the white solid was added diethyl ether, and themixture was sonicated, and filtered. The resulting material was dried ona vacuum pump to give 52.9 mg of the title compound as a white solid,67% yield. ¹H NMR: consistent with structure. MS (ion spray) 479 (M⁺).

EXAMPLE 694 1-Amino-cyclopropanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo4H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amideHydrochloride

A compound from Example 461 (94.3 mg, 0.18 mmol) was dissolved inHCl_((g))/AcOH (5 mL, ˜3N) and stirred at rt. After 1 h, additionalHCl_((g))/AcOH (5 mL, ˜3N) was added. After 5 h, the mixture wasconcentrated, followed by azeotropic removal of water with acetonitrilein vacuo (×3). To the white solid was added diethyl ether, and themixture was sonicated, and filtered. The resulting material was dried ona vacuum pump to give 70.2 mg of the title compound as a white solid,85% yield. 1H NMR: consistent with structure. MS (ion spray) 451 (M⁺).

EXAMPLE 695N-[3-(4,10-Dichloro-5-oxo-5H-benzo[h][1,6]naphthyridin-6-yl)-cyclohexylmethyl]-benzamide

To 0.045 g (0.1 mmols)ofN-{[(1R,3S)-3-(3-acetyl-4-amino-5-chloro-2-oxohydroquinolyl)cyclohexyl]methyl}benzamideand 0.03 ml (0.3 mmols) of POCl₃ were dissolved in DMF (2 ml) at 0-5° C.The reaction was allowed to warm to rt. and stirred for 30 minutes. Thereaction was then heated at 45° C. over 12 hours. The solvent wasremoved in vacuo and the residue was chromatographed on silica andeluted with EtOAc/Hexane 1:1 to 2:1 to yield 0.002 g of the titlecompound.

MS(ES+)m/z=480.

EXAMPLE 696N-[3-(10-Chloro-4-methoxy-5-oxo-5H-benzo[h][1,6]naphthyridin-6-yl)-cyclohexylmethyl]-benzamide

To 0.045 g (0.1 mmols) ofN-{[(1R,3S)-3-(3-acetyl-4-amino-5-chloro-2-oxyhydroquinolyl)cyclohexyl}methyl}benzamideand 0.03 ml (0.3 mmols) of POCl₃ were dissolved in DMF (2 ml) at 0-5° C.The reaction was allowed to warm to rt. and stirred for 30 minutes. Thereaction was then heated at 45° C. over 12 hours. The reaction wascooled to rt. and NaOMe in MeOH (0.4 mmols) was added. The reaction washeated at 60° C. for 6 hours. The solvent was removed in vacuo. Theresidue was dissolved in CH₂Cl₂ and rinsed 1 time with 1N HCl, followedby 3 times with water. The solvent was removed in vacuo and the residuewas chromatographed on silica and eluted with EtOAc/Hexane 1:1 to 2:1 toyield 0.011 g of the title compound.

MS(ES+)m/z=476.

EXAMPLE 697N-[3-(10-Chloro-4-methylamino-5-oxo-5H-benzo[h][1,6]naphthyridin-6-yl)-cyclohexylmethyl]-benzamide

To 0.005 g (0.01 mmols) of a compound from Example 696 was combined with1.0 ml of aqueous methylamine 40% (excess) in ethanol (5 ml). Thereaction was refluxed for 30 minutes. MS(ES+)m/z475.

EXAMPLE 698 R(−)Amino-acetic Acid[3-(9-chloro-3-methyl-4oxo4H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methylEster Hydrochloride

To a compound from Example 472 (96.7 mg, 0.16 mmol) was added aceticacid saturated with HCl_((g)) (10 mL, ˜3N in HCl) and the solutionstirred vigorously at rt. for 1 hour. The reaction was concentrated,followed by addition of acetonitrile and concentration to assist in theremoval of acetic acid (×2). The resulting white solid was treated withethyl ether, sonicated, and filtered to yield 68.4 mg of the titlecompound as a white solid, 79% yield. ¹H NMR: consistent with structure.MS (ion spray) 523 (M⁺).

EXAMPLE 699 S(+)Amino-acetic Acid[3-(9-chloro-3-methyl-4-oxo-4H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methylEster Hydrochloride

To a compound from Example 467 (70.0 mg, 0.11 mmol) was added aceticacid saturated with HCl_((g)) (10 mL, ˜3N in HCl) and the solutionstirred vigorously at rt. for 1 hour. The reaction was concentrated,followed by addition of acetonitrile and concentration to assist in theremoval of acetic acid (×2). The resulting white solid was treated withethyl ether, sonicated, and filtered to yield 37.84 mg of the titlecompound as a white solid, 60% yield. ¹H NMR: consistent with structure.MS (ion spray) 523 (M⁺).

EXAMPLE 700{[3-(9-Chloro-3-methyl-4oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentylcarbamoyl]-phenyl-methyl}-carbamicAcid tert-butyl Ester

A compound from Example 621 was converted to obtain the title compoundwith L-N-boc phenyl glycine as described for Example 515. ESMS: 565(M+1)+.

EXAMPLE 701{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentylcarbamoyl]-phenyl-methyl}-trifluoroacetamide

A compound from Example 621 was converted to obtain the title compoundwith L-N-trifluoroacetyl phenyl glycine as described for Example 515.ESMS: 561 (M+1)+.

EXAMPLE 703cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-(3-phenylureido)cyclohexane

To the suspension ofcis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-amino-cyclohexane(0.0446 g, 0.121 mmol) in 1 mL anhydrous THF at RT was added 2N NaOH(0.60 mL, 0.121 mmol). After 5 min. the phenylisocyanate (0.013 mL,0.121mmol). After 20 min. the reaction was diluted with EtOAc, washed withwater and concentrated to near dryness. After sonication and filtrationa white solid (0.0412, 75%) was obtained.

ESIMS m/e 451 ³⁵Cl (M⁺+1) and 453 ³⁷Cl (M⁺+1).

EXAMPLE 7042-[(3S,1R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-5H-isoquinoline-1,3-dione

To5-[(1S,3R)-3-(aminomethyl)cyclohexyl]-9-chloro-3-methyl-5-hydroisoxazolo[4,3-c]quinolin4-one(60 mg, 0.17 mmol) and homophthalic acid (38 mg, 0.21 mmol) was addedxylenes (10 mL), and the reaction heated to reflux under nitrogenovernight with a Dean-Stark trap attached to effect removal of water.The solution was concentrated and dissolved in 20%isopropanol/chloroform, washed with 1.0N HCl (×2), saturated aqueoussodium bicarbonate solution, brine, dried over sodium sulfate andconcentrated. Purification by flash chromatography on silica gel(eluting with 20-25% ethyl acetate/hexane) gave 26 mg of the titlecompound as a clear oil, 31% yield. ¹H NMR: consistent with structure.MS (ion spray) 490 (M⁺), 488 (M−1).

EXAMPLE 705 3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylicAcid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentyl]-amide

A compound from Example 620 was acylated with 2chloro-5-fluoro phenylisoxazoyl chloride to obtain the title compound as described for Example515. ESMS: 570 (M+1)⁺.

EXAMPLE 7061-tert-Butyl-3-(2-chloro-6-fluoro-phenyl)-1H-pyrazole-4-carboxylic Acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentyl]-amide

A compound from Example 620 was converted to obtain the title compoundwith 4-(2-chloro-5-fluoro phenyl)-1-t-butyl-pyrazole-3-carboxylic acidas described for Example 515. ESMS: 610 (M+1)+.

EXAMPLE 707{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentylcarbamoyl]-phenyl-methyl}-carbamicAcid tert-Butyl Ester

A compound from Example 621 was converted to obtain the title compoundwith L-N-boc phenyl glycine as described for Example 515. ESMS: 565(M+1)+.

EXAMPLE 708 1R,3S—N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentyl]-2-(3,4,5-trimethoxy-phenyl)-acetamide

A mixture of 1R,3S-5-(3-amino-cyclopentylmethyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4one(15 mg, 0.045 mmol), 3,4,5-trimethoxyphenyl acetic acid (14 mg, 0.06mmol), EDC (12 mg, 0.06 mmol) and DMAP (2 mg) dissolved in DCM (10 mL)was stirred overnight at rt. The reaction mixture was diluted withadditional DCM (10 mL), washed with aq. NaHCO₃ (sat'd, 2×20 mL), water(2×20 mL), brine (2×20 mL), dried over sodium sulfate, filtered,evaporated, and chromatographed (Bond Elut, Si, 60 cc, 50% EtOAc inhexanes) to yield the desired product (10 mg, 41%). ESMS: 540 (M+1)+.

EXAMPLE 709N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl-cyclopentyl]-2-(3,4,5-trimethoxy-phenyl)-acetamide

To a stirred solution of racemic5-(3-aminocyclopentyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one(81 mg, 0.26 mmol) in CH₂Cl₂ (3 mL) was added 3,4,5-trimethoxy phenylacetic acid (114 mg, 0.52 mmol), Et₃N (0.1 mL, 0.50 mmol), HOBt (41 mg,0.3 mmol),DMAP (catalytic amount) and EDCI (72 mg, 0.38 mmol). Thereaction mixture was stirred at r.t. for 18 hours. The mixture wasdiluted with CH₂Cl₂, washed (brine), dried (Na₂SO₄), filtered andconcentrated. Column chromatography (silica gel, hexanes/ethyl acetate,gradient) gave the racemic title compound (89 mg, 66%). Mass Spectrum(FIA) (m/z) 454.0 (M+1)

EXAMPLE 7102-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5yl)-R-cycloheptyl]-N-(3,4,5-trimethoxyphenyl)-acetamide

To a solution of 0.038 g (0.1 mmol) of2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cycloheptyl]aceticacid in THF/DMF 1-1 (5 mL) was added 0.061 g (0.44 mmol) of1-hydroxy-7-azabenzotriazole and 0.86 g (0.44 mmol) of EDCI. After 40minutes, 0.083 g (0.44 mmol) of 3,4,5-trimethoxyaniline was added. After3.25 hours, the solvent was removed in vacuo and replaced with EtOAc.The organic layer was rinsed with 1N HCl, aq. NaHCO₃, then ×3 withwater. The organic layer was dried and the solvent was removed in vacuoto yield 0.026 g of the title compound. MS(ES+)m/z=554.

EXAMPLE 7112-Acetylamino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-phenylacetamide

A compound as described in Example 633 (75 mg, 0.16 mmol) was combinedwith 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol),1-hydroxybenzotriazole hydrate (33 mg, 0.24 mmol), and glacial aceticacid (0.015 mL, 0.24 mmol) in tetrahydrofuran (6 mL) and the mixturestirred over the weekend at ambient temperature. The mixture was thenconcentrated in vacuo and the residue loaded onto a silica gel columnand eluted with methanol/dichloromethane, which allowed for isolation of82 mg (99%) of product as an off white solid. MS(ES): (M+1)⁺ 507.1,509.1 m/z.

EXAMPLE 7122-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-pyrrolidine-1-carboxylicAcid Benzyl Ester

A compound as described in Example 660 (60 mg, 0.18 mmol) was combinedwith DCC (56 mg, 0.27 mmol), HOBT (37 mg, 0.27 mmol), andN-carbobenzyloxy-L-proline (68 mg, 0.27 mmol) in tetrahydrofuran (6 mL)and the mixture stirred overnight at rt. The mixture was thenconcentrated in vacuo and the residue loaded onto a silica gel columnand eluted with MeOH/CH₂Cl₂, which allowed for isolation of 71 mg (70%)of product as a white solid. MS(ES): (M+1)⁺ 563.0, 565.0 m/z.

EXAMPLE 713 2-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-pyrrolidine-1-carboxylic Acid BenzylEster

A compound as described in Example 660 (40 mg, 0.12 mmol) was combinedwith DCC (37 mg, 0.18 mmol), HOBT (24 mg, 0.18 mmol), andN-carbobenzyloxy-D-proline (45 mg, 0.18 mmol) in tetrahydrofuran (4 mL)and the mixture stirred overnight at rt. The mixture was thenconcentrated in vacuo and the residue loaded onto a silica gel columnand eluted with MeOH/CH₂Cl₂, which allowed for isolation of 27 mg (40%)of product as a white solid. MS(ES): (M+1)⁺ 563.0, 565.0 m/z.

EXAMPLE 714 1-Benzoyl-pyrrolidine-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide

A compound as described in Example 660 (40 mg, 0.12 mmol) was combinedwith EDC, HOBT (25 mg, 0.18 mmol), and the compound from preparation 104(40 mg, 0.18 mmol) in tetrahydrofuran (6 mL) and the mixture stirredovernight at rt. The mixture was then concentrated in vacuo and theresidue loaded onto a silica gel column and eluted with EtOAc, whichallowed for isolation of 58 mg (90%) of product as a white solid.MS(ES): (M+1)⁺ 533.3, 5535.3 m/z.

EXAMPLE 715 1-Phenylacetyl-pyrrolidine-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide

A compound as described in Example 660 (40 mg, 0.12 mmol) was combinedwith EDC (37 mg, 0.18 mmol), HOBT (25 mg, 0.18 mmol), and the compoundfrom preparation 8R (42 mg, 0.18 mmol) in tetrahydrofuran (5 mL) and themixture stirred over the weekend at rt. The mixture was thenconcentrated in vacuo and the residue loaded onto a silica gel columnand eluted with EtOAc, which allowed for isolation of 54 mg (82%) ofproduct as a white solid. MS(ES): (M+1)⁺ 547.1 m/z.

EXAMPLE 716 1-Benzyl-pyrrolidine-2-carboxylic Acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide

A compound as described in Example 660 (40 mg, 0.12 mmol) was combinedwith DCC (37 mg, 0.18 mmol), HOBT (25 mg, 0.18 mmol), and the compoundfrom preparation 107 (49 mg, 0.24 mmol) in tetrahydrofuran (5 mL) andthe mixture stirred over the weekend at rt. The mixture was thenconcentrated in vacuo and the residue loaded onto a silica gel columnand eluted with MeOH/CH₂Cl₂. A repeat of the chromatography yielded thetitle compound (56 mg, 89%). MS(ES): (M+1)⁺ 519.3, 520.3 m/z.

EXAMPLE 717N-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-methyl}-2-phenyl-acetamide

5-(3-Amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydroiodide (70 mg, 0.19 mmol) was combined with EDC (47 mg, 0.25 mmol),1-hydroxy-7-azabenzo-triazole (34 mg, 0.25 mmol), N,N-diisopropylethylamine (0.10 mL, 0.58 mmol), DMAP (5 mg, cat.), and N-benzylglycinehydrochloride (50 mg, 0.25 mmol) in DMF(6 mL) and the mixture stirredovernight at rt. The mixture was then concentrated in vacuo and theresidue taken up in chloroform/MeOH and the organic solution washed withaqueous NaHCO₃. The organic solution was dried over Na₂SO₄ andconcentrated in vacuo. The residue was loaded onto a silica gel columnand eluted with MeOH/CH₂Cl₂, which allowed for the recovery of 32 mg(35%) of the free base. This material was dissolved in minimal EtOAc andtreated with excess diethyl ether/hydrochloric acid. Concentration ofthis mixture to dryness allowed for quantitative recovery of thehydrochloride salt as an off white solid. MS(ES): (M+1)⁺ 479.1, 481.2.

EXAMPLE 718 1-methyl-piperidine-4-carboxylic Acid{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methyl}-amide

A product from Example 638 (50 mg; 0.108 mmol) was dissolved inanhydrous dimethylformamide (10 mL) under a nitrogen atmosphere, mixedwith 1-methyl-piperidine-4-carboxylic acid hydrochloride (58.0 mg; 0.323mmol; 3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (61.8 mg; 0.323 mmol; 3 equiv), 2,4,6-trimethylpyridine(86 μL; 0.645 mmol; 6 equiv), and 1-hydroxy-7-azabenzotriazole (43.9 mg;0.323 mmol; 3 equiv), and stirred overnight at room temperature. Thereaction solution was diluted with 2 volumes ethyl acetate, 10 volumeswater, and 1 volume saturated NaHCO_(3(aq)). The organic layer wasseparated and then washed with saturated NaCl_((aq)), dried overNa₂SO_(4(S)), filtered, and concentrated in vacuo. The resultingmaterial was purified by radial chromatography on a 2 mm thick silicagel rotor with a 2% then 4% methanol/dichloromethane (v/v) mobile phaseand finally a 2% methanol/0.5% triethylamine/dichloromethane (v/v/v)mobile phase. The desired product was isolated as a white solid in 74%yield (47 mg).

EXAMPLE 719N-[3-(9-Acetylamino-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-benzamide

To a solution of a compound from Example 667 (0.025 g, 0.06 mmol) andAcOH (0.02 mL, 0.36 mmol) in DMF (1 mL) under N₂ was added EDCI (0.023g, 0.12 mmol) and DMAP (0.002 g, 0.01 mmol). The solution was stirredovernight, diluted with EtOAc, washed (H₂O then brine), dried (MgSO₄),filtered, and concentrated. Flash chromatography (silica gel,acetone/CH₂Cl₂ gradient) gave the title compound (0.023 g, 82%). MassSpectrum (ES+) (m/z) 473.3 [M+1]

EXAMPLE 720N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-phenylamino-acetamide

Anhydrous dimethylformamide (10 mL) in a nitrogen atmosphere was used todissolve5-(3-aminocyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one(50 mg; 0.151 mmol), N-phenylglycine (29.6 mg; 0.196 mmol; 1.3 equiv),1-hydroxy-7-azabenzotriazole (26.7 mg; 0.196 mmol; 1.3 equiv),1-[3-(dimethylamino)propyl[-3-ethylcarbodiimide hydrochloride (37.6 mg;0.196 mmol; 1.3 equiv), and 2,4,6-trimethylpyridine (199 μL; 1.51 mmol;10 equiv). After overnight stirring at room temperature, the reactionsolution was treated in a manner similar to Example 159. The resultingmaterial was purified by three consecutive radial chromatography runs ona 2 mm thick silica gel rotor with a 1% methanol/dichloromethane (v/v)mobile phase, a 1% methanol/0.25% triethylamine/dichloromethane (v/v/v)mobile phase, and a 5% acetonitrile/dichloromethane mobile phase. Thedesired product was isolated as a white solid 56% yield (30 mg). MS(ES)calc'd: [M+M]⁺=465.16 m/z; [M−H]⁻=463.16 m/z; [M+OAc]⁻=523.16 m/z.Found: 465.1 m/z; 463.2 m/z; 523.2 m/z.

EXAMPLE 7212-[3R-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cycloheptyl]-N-(3,4,5-trimethoxyphenyl)-acetamide

In a manner similar to the preparation of Example 710, 0.055 g (0.14mmol) of a compound from Example 680 was converted to a residue whichwas chromatographed on silica with EtOAc/hexanes 1/1 to yield 0.044 g ofthe title compound. MS(ES+)m/z=553.9.

EXAMPLE 7226-Chloro-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylmethyl]-nicotinamide

A solution ofcis-5-[3-(aminomethyl)cyclohexyl]-9-chloro-3-methyl-5-hydroisoxazolo[4,5-c]quinolin4-one(0.188 g, 0.54 mmol) and 6-chloro-nicotinic acid (0.103 g, 0.65 mmol) inDMF (10 mL) was treated with EDCI (0.125 g, 0.65 mmol) and HOAt (0.089g, 0.65 mmol). The reaction was then treated with excess Et₃N (0.167 g,1.62 mmol) and DMAP (6 mg, 0.05 mmol) and stirred at room temperatureovernight. The reaction was concentrated to a solid and then taken up in20% isopropanol in CHCl₃ (100 mL). This solution was transferred to aseparatory funnel and washed with a saturated sodium bicarbonatesolution (3×50 mL) and brine (2×50 mL). The organic solution was driedover sodium sulfate, filtered, and the solvent removed to afford a crudeyellow solid. The solid was purified using silica gel columnchromatography. The product was eluted using 50% EtOAc in CHCl₃. Thesolvent was removed in vacuo to afford 0.150 g (57%) of product as anoff white solid. MS m/z (ES+) 484.8 (M+H)⁺, (ES−) 482.8 (M—H), 542.8(M+CH3COO⁻)⁻.

EXAMPLE 7232-tert-butylamino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-pyridin-3-yl-acetamide

A compound from preparation 341 was saponified over 2 h with LiOH (1.5equiv in water subsequently mixed with 1,4-dioxane). The carboxylic acidwas isolated by rotary evaporation of the solution to dryness,acidification to pH 2 with 1 N HCl (aq), rotary evaporation of thesolution to dryness, and overnight drying at 0.1 torr. This material(1.3 equiv) was mixed with the free base of material from Preparation210 (100 mg; 0.301 mmol) in anhydrous DMF. Diisopropylethylamine (262μL; 0.392 mmol; 5 equiv),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (75.1 mg;0.392 mmol; 1.3 equiv), and 1-hydroxy-7-azabenzotriazole (53.3 mg; 0.392mmol; 1.3 equiv) were then added and the solution was stirred overnight,at rt. EtOAc (70 mL) and saturated NaHCO₃ (aq)(10 volumes) were addedand the organic layer was separated, washed with saturated NaCl(aq)(once), dried with Na₂SO₄ filtered, and concentrated in vacuo. Afterpurification by radial chromatography, 34 mg off-white solid wasisolated (22% yield). MS(ES) calc'd: [M+H]⁺=522.2 m/z; [M−H]⁻=520.2 m/z.Found: 522.2 m/z; 520.3 m/z.

EXAMPLE 724N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(2,2-dimethyl-propylamino)-2-pyridin-3-yl-acetamide

A compound from preparation 341 was used in a manner similar to Example723 (substituting triethylamine for diisopropylethylamine) to preparethe title compound (24 mg white solid; 15% yield). MS(ES) calc'd:[M+H]⁺=536.2 m/z. Found: 536.2 m/z.

EXAMPLE 725N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(4-methyl-piperazin-1-yl)-2-pyridin-3-yl-acetamide

A compound from preparation 343 was used in a manner similar to Example723 (substituting Et₃N for diisopropylethylamine) to prepare the desiredproduct A 1% then 2% then 3% methanol/chloroform/trace Et₃N (v/v/v)mobile phase on a 2 mm chromatotron rotor was used to purify the desiredproduct (129 mg white solid; 78% yield). MS(exact mass) calc'd:[M+H]⁺=594.2381 m/z. Found: 594.2385 m/z.

EXAMPLE 7262-(Benzenesulfonyl-pyridin-2-yl-amino)-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-acetamide

To a solution of5-(3-amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydroiodide, 130 mg (0.28 mmol) in 10 mL of DMF was added 82 mg (0.28mmol) of (benzenesulfonyl-pyridin-2-yl-amino)-acetic acid (Bionet), 46mg (0.34 mmol) of 1-hydroxy-7-azabenzo-triazole, 66 mg (0.34 mmol) ofEDC, 5 mg of DMAP and 120 μL (0.84 mmol) of TEA. The reaction mixturewas stirred six days at rt. and was concentrated to dryness. The residuewas dissolved in 20% isopropanol/chloroform, washed with saturatedNaHCO₃, washed with brine, dried over Na₂SO₄, filtered and concentratedto dryness. The residue was purified by radial chromatography using aMeOH/chloroform gradient and concentrated to dryness. The residue wasslurried in ether/hexanes and concentrated to dryness to yield 79 mg(47%) of the title compound as a tan foam. MS (ion spray) 606.1 (M+).

EXAMPLE 727N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexyl]-2-hydroxy-2-phenyl-acetamide

A solution of a compound from preparation 380 (0.08 g, 0.24 mmol),R-Mandelic acid (0.04 g, 0.29 mmol), EDCI (0.06 g, 0.29 mmol), HOAt(0.04 g, 0.29 mmol) in DMF (10 mL) was treated with Et₃N (0.07 g, 0.7mmol) and DMAP (3.0 mg, 0.02 mmol) and stirred overnight at roomtemperature. The solution was then diluted in EtOAc (50 mL) and washedwith 5% citric acid (3×10 mL), sat'd sodium bicarbonate (3×10 mL), andbrine (2×10 mL). The solution was dried over sodium sulfate and purifiedby silica gel column chromatography. The solvent was removed in vacuo toafford 0.08 g (74%) as a white solid.

EXAMPLE 728N-{[3-(9-Chloro-3-methyl-4oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-methyl}-nicotinamide

5-(3-Amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-onehydroiodide (70 mg, 0.19 mmol) was combined with EDC (47 mg, 0.25 mmol),1-hydroxy-7-azabenzo-triazole (34 mg, 0.25 mmol), N,N-diisopropylethylamine (0.10 mL, 0.58 mmol), (5 mg, cat.), and nicotinuric acid (44 mg,0.24 mmol) in DMF(6 mL) and the mixture stirred overnight at rt. Themixture was then concentrated in vacuo and the residue taken up in waterand extracted with EtOAc. The combined extracts were dried over Na₂SO₄and concentrated in vacuo. The residue was loaded onto a silica gelcolumn and eluted with MeOH/CH₂Cl₂ which allowed for the recovery of 87mg (92%) of the title compound as a white solid.

MS(ES): (M+1)⁺ 494.1, 496.1.

EXAMPLE 729N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-dimethylamino-2-pyridin-3-yl-acetamide

A compound from preparation 342 was used in a manner similar to Example723 (substituting Et₃N for diisopropylethylamine) to prepare the desiredproduct. A 1% methanol/chloroform/trace triethylamine (v/v/v) mobilephase on a 2 mm chromatotron rotor was used to purify the desiredproduct (112 mg white solid; 76% yield). MS(exact mass) calc'd:[M+H]⁺=494.1959 m/z. Found: 494.1978 m/z.

PREPARATION 406 Pyridin-3-yl-(pyridin-2-yloxy)-acetic Acid Ethyl Ester

A typical synthesis of bromopyridin-3-ylacetic acid ethyl ester isdescribed: A solution of fresh lithium diisopropylamide (LDA) wasprepared at −10° C. from diisopropylamine (8.54 mL; 60.5 mmol) andn-butyllithium (37.8 mL of a 1.6 M hexanes solution; 12.1 mmol) andstirred for 10 min. After chilling the fresh LDA to −78° C., ethyl3-pyridylacetate (9.21 mL; 60.5 mmol) was added and the solution wasstirred another 10 min. Chlorotrimethylsilane (7.68 mL; 60.5 mmol) wasadded to the resulting opaque yellow slurry and the solution was stirred5 min. Finally a solution of 4-(dimethylamino)pyridinium tribromide(22.0 g; 60.5 mmol) in tetrahydrofuran was added and the reactionsolution was stirred 10 min. After warming to room temperature thereaction solution was quenched with saturated NH4Cl_((aq)) and extractedtwice with ethyl acetate. The combined organic layer was washed oncewith saturated NaCl_((aq)), dried with Na₂SO_(4(S)), filtered, andconcentrated in vacuo. The resulting bromopyridin-3-ylacetic acid ethylester was an unstable brown oil and was therefore used immediately.

Silver carbonate (2.79 g; 10.1 mmol; 0.5 equiv) was refluxed in toluene(40 mL) for 0.5 h with 2-hydroxypyridine (1.92 g; 20.2 mmol; 1.0 equiv)and an aliquot of bromo-pyridin-3-yl-acetic acid ethyl ester (approx.4.9 g; 20.2 mmol), prepared as described above. After cooling to roomtemperature and filtration of the reaction mixture, the supernatant waswashed with saturated NaHCO_(3(aq)) (1×), water (1×), and saturatedNaCl_((aq)) (1×). The organic layer was dried over Na₂SO_(4(S)),filtered, and concentrated in vacuo. Silica chromatography with a 35%ethyl acetate/hexanes mobile phase produced a yellow oil (1.14 g; 22%yield) that solidified upon standing. MS(ES) calc'd: [M+H]⁺=259.2 m/z;[M−M]⁻=257.2 m/z. Found: 259.1 m/z; 257.2 m/z. REFERENCE: U. Schöllkopf,I. Hoppe, Justus Liebigs Ann. Chem. (1972) 765, 153-170.

EXAMPLE 730 PREPARATION a 1,3-cyclohexanedicarboxylic Acid

To a suspension of isophthalic acid (500 g, 3 mol) in methanol (2.8) wasadded 5% Rhodium-on-alumina catalyst (50 g) and acetic acid (150 ml).The reaction mixture was shaken under hydrogen (50 psi) at roomtemperature overnight. The mixture was filtered through celite. To thissolution was added fresh 5% Rhodium-on-alumina catalyst (25 g), and themixture was shaken under 50 psi of hydrogen for another 24 hours. Thefinal reaction mixture was filtered through celite. The solution wasconcentrated under vacuum to give 493 g of the title compound as a whitepowder (96.3% yield). m.p. 163-165° C.

PREPARATION b 3-Oxabicyclo[3.3.1]nonane-2,4-dione

A solution of dicyclohexylcarbodiimide (200 g, 1.16 mol) in CH₂Cl₂ (1000ml) was added dropwise to a suspension of compound from preparation a(257 g, 1.25 mol) in CH₂Cl₂ (550 ml), and the mixture was stirred atroom temperature for 4 hours. The precipitated dicyclohexylurea wasfiltered and washed several times with cold CH₂Cl₂ (200 ml×3). Thecombined organic layer was concentrated to give a white solid, which wassuspended in MTBE (900 ml). This solid was collected by filtration,washed with MTBE (250 ml), and dried under house vacuum to give thetitle compound (137 g). The filtrate was concentrated to a residue,which was suspended in MTBE (250 ml) to give another 31 g anhydride. Thetotal yield was 168 g (94%). m.p. 138-140° C.

PREPARATION c cis-1,3-Cyclohexanedicarboxylic Acid Diethyl Ester

To a solution of compound from preparation b (31 g, 0.2 mol) in ethanol(anhydrous, 310 ml) was added p-toluenesulfonic acid monohydrate (1.9 g,10 mmol, 0.05 equiv.) and triethyl orthoformate (50 ml, 0.3 mol). Thereaction mixture was stirred at 60° C. overnight. The volatiles werestripped and the residue was diluted with ethyl acetate (250 ml), washedwith water (120 ml) and brine (100 ml), and dried over MgSO₄. Afterfiltration and evaporation, the residue was purified by chromatography.Eluting the column with 10% ethyl acetate in hexane afforded the titlecompound (40 g, 87.7% yield).

¹H NMR: (500 MHz, CDCl₃) δ 4.11 (q, J=7.0 Hz, 4H), 2.29 (dt, 2H), 2.11(dd, 1H) 1.97 (m, 2H), 1.98 (m, 1 H), 1.53 (q, J=12.5 Hz, 2H), 1.30-1.40(m, 2H), 1.25 (t, J=7.0 Hz, 6H).

PREPARATION d 1,3-Cyclohexanedicarboxylic Acid, Monoethyl Ester (1R, 3S)

To a suspension of compound from preparation c (40 g, 17.5 mmol) in pH7.2 phosphate buffer [0.2 M](1.21) was added lipase AY30 (Amano, 16.7g). The mixture was stirred vigorously at room temperature for 30 hours.The mixture was acidified with 10-15% HCl to pH<2, and extracted withethyl acetate (500 ml×2). The combined organic solution was washed withaqueous 10% Na₂CO₃ (100 ml×2) and water (100 ml×2). The combined aqueouslayers were washed again with ethyl acetate (150 ml) and then acidifiedwith 10-15% HCl to pH<2. The acidified aqueous was then extracted withethyl acetate (150 ml×3). The combined organic solution was dried overMgSO₄. After filtration and concentration the title compound (35.6 g,100% yield) was obtained.

¹H NMR (500 MHz, CDCl₃) δ 4.12 (q, J=7.0 Hz, 2H), 2.20-2.40 (m, 3H),1.85-2.05 (m, 3H), 1.5 (q, 2H), 1.35 (m, 2H), 1.24 (t, J=7.0 Hz, 3H).

PREPARATION e Ethyl-[3-N-(methylcarbamate)-cyclohexyl]-carboxylate (1R,3S)

A solution of a compound from preparation d (73 g, 365 mmol) in toluene(750 ml) was heated to reflux using a Dean-Stark trap to separate traceamounts of water. After collecting about 10 ml of water, the mixture wascooled down to about 40-50° C. To this mixture was added triethylamine(56 ml, 0.4 mol), and diphenylphosphoryl azide (86.5 ml, 0.4 mol). Thereaction mixture was stirred at 110° C. for 60 min, cooled to 70° C.,and methanol (64 g, 2 mol ) was added with stirring. After addition, thefinal reaction mixture was then heated to 85° C. overnight. Aftercooling to room temperature, the mixture was diluted with ethyl acetate(700 ml) and washed with water (500 ml). The aqueous layer was extractedwith ethyl acetate (500 ml×2). The combined organic solution was washedagain with water (500 ml) and brine (500 ml). After drying over MgSO₄and concentration under reduced pressure, the title compound wasobtained as a colorless oil (86 g, 100%).

¹H NMR: (300 MHz, CDCl₃) δ 4.60 (sb, 1H), 4.13 (q, 2H), 3.65 (s, 3H),3.50 (sb, 1H), 2.38 (t, 1H), 2.23 (d, 1H), 2.00−1.80 (m, 3H), 1.24 (t,3H), 1.12−0.95 (m, 1H).

PREPARATION f Ethyl-((1R,3S)-3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl-amino}cyclohexyl)-carboxylate

To a solution of compound from preparation e (86 g, 365 mmol) in CH₂Cl₂(750 ml) was added iodotrimethylsilane (100 g, 500 mmol) in one portion,at room temperature. The reaction mixture was stirred for 2 hours atambient temperature, cooled to 0-5° C., and methanol (50 ml) was added.After stirring 15 minutes, the solution was concentrated under reducedpressure. The residue was dissolved in THF (1l). To this solution wasadded water (0.51), potassium carbonate (138 g, 1 mol), and a solutionof 3-(6-fluoro-2-chlorophenyl)-5-methylisooxazole-4-carboxyl chloride(10 g, 0.4 mol) in 250 ml THF, dropwise. After the addition, thereaction mixture was heated to room temperature and stirred for 12hours. THF was removed under house vacuum, water (250 ml) was added, andthe mixture was extracted with ethyl acetate (500 ml×3). The combinedorganic solution was washed with saturated sodium thiosulfate (150 ml),water (500 ml), brine (500 ml) and then dried over MgSO₄. Afterfiltration and evaporation under vacuum, the residue was purified byrecrystallization from ABE (250 ml). Repeating this recrystallizationprocedure three times provided the title compound (122.7 g, 82.5% yield)as a white powder.

IR: ν_(max) (film) 3429, 3011, 2940, 1725, 1662, 1187 cm⁻¹.

PREPARATION g Ethyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-carboxylate

To a solution of compound from preparation f (78 g, 190 mmol) in DMF(750 ml) was added a solution of KHMDS ([0.5M], 400 ml, 200 mmol). Thetemperature was kept at 25° C. by using an ice-bath. After the additionwas complete, the reaction mixture was analyzed by TLC (silica gel, 50%EtOAc in hexane) and found to be complete. Water (1 l) was added and themixture was extracted with EtOAc (800 ml×3). The combined organicsolution was washed with 1N HCl (250 ml), water (250 ml), brine (250ml), dried over MgSO₄ and concentrated to give a residue which waspurified by recrystallization from MTBE (500 ml) to afford 66 g of thetitle compound as a light yellow powder (89.0% yield).

IR: ν_(max) (film) 3030, 1720, 1670, 1220 cm⁻¹.

PREPARATION h (1R, 3S)3-(9-chloro-3-methyl-4oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylCarboxylic Acid

To a solution of compound from preparation g (62 g, 160 mmol) in THF(600 ml) was added 5N aqueous sodium hydroxide (120 ml) at roomtemperature. The reaction mixture was heated to 60° C. for 15 hours withstirring. After cooling to room temperature, water (750 ml) was addedand the mixture was washed with ethyl acetate (500 ml). The aqueousphase was separated and acidified with 15% HCl to pH<2. The aqueousphase was then extracted with methylene chloride (1000 ml×3). Thecombined organic extracts were washed again with water (500 ml), brine(500 ml), and dried over MgSO₄. After filtration and evaporation undervacuum, the dark brown residue was suspended in MTBE (1000 ml), andrefrigerated overnight. The mixture was filtered to afford 55.45 g(96.4%) of bright yellow product.

IR: ν_(max) (Film) 3200, 2936, 1726, 1643, 1595, 1173 cm⁻¹.

PREPARATION i 2-methyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]carbamate

To a suspension of compound from preparation 8 (55.4 g, 154 mmol) intoluene (1l) was added triethylamine (23.7 ml, 170 mmol), anddiphenylphosphoryl azide (36.5 ml, 170 mmol). The reaction mixture wasstirred at 110° C. for 2 hours during which time a solution formed. Thesolution was cooled to 80° C. and methanol (25 g, 0.77 mol) was addedwith stirring. The solution was warmed to 85° C. for 22 hours. Aftercooling to room temperature, the toluene was removed under reducedpressure and the residue was dissolved in dichloromethane (3l) andwashed with water (1l). The aqueous phase was extracted withdichloromethane (1l×2) and the combined organic solution was washedagain with water (500 ml) and brine (500 ml). After drying over MgSO₄,the solution was concentrated under vacuum. The crude product waspurified by crystallization (CH₂Cl₂/MTBE, 0.5 ½ l) to afford the titlecompound (46.6 g, 78.2%). [α]_(D)+49.2°, [α]₃₆₅+263.3° (c, 0.56; CHCl₃).The filtrate was concentrated to a residue, which was purified bychromatography to obtain a second crop of product (5.1 g). The totalyield was 86.8%.

IR ν_(max) (Film) 3410, 3020, 2950, 1710, 1670, 1220 cm⁻¹.

PREPARATION j (1R, 3S)3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylMethyl Alcohol

To a solution of compound from preparation h (4.4 g, 12.2 mmol) in THF(45 ml) was added borane-methyl sulfide complex (2.0 M solution in THF,12.5 ml, 25 mmol) dropwise at 0° C. When the addition was complete, thereaction mixture was allowed to warn to room temperature and was stirredfor one hour. Methanol (10 ml) was added slowly (gas generated) withstirring. The reaction mixture was then poured into ice-water (60 ml)and extracted with ethyl acetate (100 ml×3). The combined organicsolution was washed with 1N HCl (50 ml), brine (50 ml), and dried overMgSO₄. After filtration and evaporation under vacuum, the yellow titlecompound (4.34 g, 100%) was obtained. M.S.: m/z 347 (M⁺+1).

PREPARATION k (1R, 3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylMethyl Alcohol Mesylate

To a stirred solution of compound from preparation j (4.32 g. 12.5 mol)in pyridine (25 ml) was added DMAP (10 mg) and methanesulfonyl chloride(1.16 ml, 15 mmol, 1.2 equiv) and the resulting mixture was stirred atroom temperature for 1.5 h. Water (100 ml) was added, and the mixturewas extracted with ethyl acetate (150 ml×2). The combined organicextracts were washed again with brine (100 ml), dried (MgSO₄) andconcentrated. The residue was suspended in MTBE (25 ml) and filtered toobtain the title compound as a solid (4.65 g, 87.8%).

[α]_(D)+8.71°, [α]₃₆₅+58.7° (c, 0.358; CHCl₃).

PREPARATION m (1R, 3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylMethyl Azide

A mixture of a compound from preparation k (4.6 g, 10.8 mmol), sodiumazide (2.15 g, 33 mmol) and DMF (45 ml) was heated to 60° C. and stirredfor 24 h. After cooling to room temperature, the mixture was poured into150 ml of ice-water and extracted with MTBE (200 ml×2). The combinedorganic extracts were washed with brine (150 ml) and dried over MgSO₄.After filtration and concentration, the residue was chromatographed onsilica gel using 30% ethyl acetate/hexane to give the title compound asa white powder (3.82 g, 95%).

[α]_(D)+17.2°, [α]₃₆₅+105.7° (c, 0.864; CHCl₃).

PREPARATION n (1R, 3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylMethyl Amine

To a solution of a compound from preparation m (2.0 g, 5.4 mmol) inethyl acetate (25 ml) was added 5% Pd/C catalyst (200 mg). The reactionmixture was shaken under hydrogen (50 psi) at room temperature for 2days. The mixture was filtered through celite and the filtrate wasconcentrated under vacuum to give the title compound as a solid (1.85 g,99.2%).

¹H NMR: (300 MHz, CDCl₃) δ 7.45 (t, 1.5H), 7.34 (d, 1.5H), 2.90 (s, 3H),2.62 (m, 2H), 2.59 (br s, 1H), 2.42 (br s, 1H), 2.00 (m, 1H), 1.84 (m,4H), 1.50 (m, 2), 1.12 (m, 1H).

PREPARATION o Ethyl-((1R,3S)-3-{[5-(2-chloro-6-fluorophenyl)-3-methylisoxazol-4-yl]carbonyl-amino}cyclohexyl)-carboxylate

To a solution of a compound from preparation d (42 g, 182 mmol) inCH₂Cl₂ (400 ml) was added iodotrimethylsilane (36.5 ml, 255 mmol) in oneportion at room temperature. The reaction mixture was stirred for 2hours at ambient temperature and then cooled down to 0-5° C. To thismixture was added methanol (50 ml) and the mixture was stirred 15minutes and concentrated under reduced pressure. The residue wasdissolved in THF (300 ml), and water (150 ml) and potassium carbonate(62 g, 0.45 mol) were added. To the resulting mixture was slowly added asolution of 5-(2-chloro-6-fluorophenyl)-3-methyl-isooxazole-4-carboxylchloride (50 g, 182 mmol) in 50 ml of THF. After the addition, thereaction mixture was allowed to warm to room temperature and was stirredfor 12 hours. THF was removed under house vacuum, water (150 ml) wasadded and the mixture was extracted with ethyl acetate (500 ml×2). Thecombined organic solution was washed with water (250 ml), brine (250 ml)and dried over MgSO₄. After filtration and evaporation under vacuum, theresidue was purified by silica gel chromatography (30% ethyl acetate inhexane) to obtain the title compound (62.57 g, 84.3% yield) as a whitepowder.

M.S.: m/z 409 (M⁺, 100%).

PREPARATION p Ethyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexyl]-carboxylate

To a 0-5° C. solution of a compound from preparation o (61.5 g, 0.15mol) in DMF (500 ml) was added a solution of KHMDS (340 ml, [0.5M], 0.17mol) in toluene. After the addition was complete, the mixture wasstirred at ambient temperature for 15 minutes and analyzed by TLC(silica gel, 50% EtOAc in hexane), which indicated completion of thereaction (TLC showed a minor by-product spot along with the majorproduct spot). Water (1 l) was added and the mixture was extracted withEtOAc (800 ml×3). The combined organic extracts were washed with water(250 ml), brine (250 ml), dried over MgSO₄ and concentrated to aresidue. The residue was purified by recrystallization from MTBE (200ml) to obtain 28.12 g of the title compound. The filtrate wasconcentrated and purified by silica gel chromatography to obtain anadditional 12.4 g of the title compound (40.52 g total, 69.3% yield).

M.S.: m/z 389 (M⁺+1, 100%).

PREPARATION q (1R, 3S)3-(9-chloro-3-methyl-4oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylCarboxylic Acid

To a solution of a compound from preparation p (40 g, 103 mmol) in THF(350 ml) was added 5N aqueous sodium hydroxide (88 ml) at roomtemperature. The reaction mixture was warmed to 60° C. and stirred for15 hours. After cooling to room temperature, water (500 ml) was addedand the mixture was washed with ethyl acetate (500 ml). The aqueousphase was separated and acidified with 15% HCl to pH<2. The precipitatewas collected by filtration and washed with ethyl acetate (250 ml). Thefiltrate was extracted with ethyl acetate (500 ml) and the combinedorganic solution was washed again with water (200 ml), brine (200 ml),and dried over MgSO₄. After filtration and evaporation under vacuum, theresidue was combined with the precipitate obtained from acidification ofthe reaction mixture and suspended in MTBE (500 ml). The suspension wasfiltered to afford the title compound as a bright yellow product (36.0g, 100%).

M.S.: m/e 361 (M⁺+1, 100%);

PREPARATION r (1R, 3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylMethyl Alcohol

To a suspension of a compound from preparation q (37.52 g, 0.104 mmol)in THF (350 ml) was added borane-methyl sulfide complex in 140 ml of THF(26 ml, 0.27 mol) dropwise at 0° C. After the addition, the reactionmixture was stirred at 0-5° C. for one hour. TLC (3:1 EtOAc/hexane)indicated the completion of the reaction. Methanol (50 ml) was addedslowly (gas generated) with stirring, followed by aqueous 10% HCl (50ml). After stirring for 15 minutes, the reaction mixture was poured intoice water (250 ml) and extracted with ethyl acetate (350 ml×2). Thecombined organic solution was washed with brine (300 ml), dried overMgSO₄ and concentrated under vacuum. The crude product was purified bysilica gel chromatography (EtOAc/hexane, 1:1) to give the title compound(32.5 g, 90%).

M.S.: m/e 347 (M⁺+1).

PREPARATION s (1R, 3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylMethyl Alcohol Mesylate

To a stirred solution of a compound from preparation r (32.25 g. 93.2mmol) in pyridine (270 ml) was added DMAP (20 mg) and methanesulfonylchloride (7.9 ml, 102 mmol, 1.1 equiv.). The mixture was stirred at roomtemperature for 1.5 hours. Water (500 ml) and EtOAc/MTBE (500 ml, 1:1)were added causing the product to precipitate. The solid was collectedby filtration, washed with MTBE (150 ml) and dried under vacuum toprovide 29.35 g as a white powder. The filtrate was washed again withbrine (300 ml), dried (MgSO₄), and concentrated. The residue wassuspended in MTBE (50 ml) and filtered to give a second crop of thetitle compound (9.5 g, total yield: 38.8 g, 99.3%).

M.S.: m/e 425 (M⁺+1).

PREPARATION t (1R, 3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylMethyl Azide

A mixture of a compound from preparation s (38.2 g, 90 mmol), sodiumazide (21 g, 0.32 mol), and DMF (350 ml) was heated to 60° C. withstirring for 20 hours. After cooling to room temperature, the mixturewas poured into ice-water (500 ml) and extracted with EtOAc (500 ml×2).The combined organic phases were washed with brine (250 ml) and driedover MgSO₄. After filtration and evaporation, the residue waschromatographed on silica gel using 30% ethyl acetate/hexane to give thetitle compound as a white powder (28.2 g, 84.4%).

M.S.: m/e 372 (M⁺+1).

PREPARATION u 1,3-cyclohexanedicarboxylic Acid

To a suspension of isophthalic acid (5.0 g, 30.1 mmol) in 45 ml ofacetic acid was added a slurry of 0.1 g of platinum oxide in 5 ml ofacetic acid. The resulting mixture was stirred under 50 psi of hydrogenat 25° C. for 16 hours. NMR analysis (DMSO-d₆) at this time showedcomplete reduction of starting material. The reaction mixture wasfiltered through Celite and the filter cake was rinsed with methanol.The combined filtrate and washes were concentrated under reducedpressure, using heptane to azeotropically remove residual acetic acid.Trituration of the resultant semi-solid with heptane and filtration ofthe precipitate provided 4.92 g (95%) of the title compound as a whitepowder. mp: 163-165° C.

PREPARATION v 3-Oxabicyclo[3.3.1]nonane-2,4-dione

A suspension of 1,3-cyclohexanedicarboxylic acid (490 g, 2.88 mol) inacetic anhydride (1500 ml) was heated to 140° C., refluxing for 2 hours.Acetic anhydride was then removed with distillation (oil bath 180° C).To the residue was added acetic anhydride (1000 ml) and refluxed at 140°C. for 1 hour. The acetic anhydride was removed again with distillation(under house vacuum, about 50° C.). After crystals appeared, the mixturewas cooled to room temperature and MTBE (400 ml) was added. The mixturewas then cooled to 0-5° C. The crystals were filtered, washed with MTBE(250 ml), and dried under house vacuum to give the title compound (382g). The filtrate was concentrated to a residue and suspended in MTBE(100 ml) to give the second crop of the title compound (14.0 g). Thetotal yield was 396 g (90.5%). Mp 138-140° C.

EXAMPLE A Benzoyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]amide

To a solution of the compound from preparation i (160 mg, 0.41 mmol) inCH₂Cl₂ (3 ml) was added iodotrimethylsilane (124 mg, 0.62.mmol) in oneportion, at room temperature. The reaction mixture was stirred for 2hours at ambient temperature and cooled to 0-5° C. Methanol (1 ml) wasadded and the mixture was stirred for 15 minutes and concentrated underreduced pressure. The residue was dissolved in THF (2 ml). To thissolution was added water (1 ml), potassium carbonate (210 mg, 1.5 mmol),and benzoyl chloride (60 ml, 0.5 mmol). The resultant mixture wasstirred at room temperature for 2 hours. THF was removed under housevacuum, water (15 ml) was added, and the mixture was extracted withethyl acetate (15 ml×2). The combined organic extracts were washed withsaturated sodium thiosulfate (10 ml), brine (10 ml) and dried overMgSO₄. After filtration and evaporation under vacuum, the residue waspurified by silica gel chromatography (35% EtOAc/hexane) to obtain thetitle compound (145 mg, 81.0% yield) as an off-white powder.

¹H NMR: (300 MHz, DMSO-d₆) δ 8.40 (d, 1H), 7.82 (m, 4H), 7.62 (t, 1H),7.43 (m, 4H), 4.5 (br s, 1H), 4.05 (m, 1H), 2.82 (s, 3H), 2.78 (m, 1H),1.88 (m, 4H), 1.71 (m, 2H), 1.60 (m, 1H), 1.41 (m, 1H).

EXAMPLE B 4-Fluoro-3-pyridyl-carboxyl-(1R, 3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylMethyl Amide

To a solution of a compound from preparation n (466 mg, 1.35 mmol) inTHF/H₂O (5 ml/2.5 ml) was added potassium carbonate (690 mg, 5 mmol) and2-fluoro-pyridin-4-carboxyl chloride (240 mg, 1.5 mmol) at roomtemperature. After the addition, the reaction mixture was stirred for 2hours at ambient temperature. Water (50 ml) was added and the mixturewas extracted with dichloromethane (50 ml×2). The combined organicextracts were washed with water (35 ml), brine (35 ml) and dried overMgSO₄. After filtration, the filtrate was concentrated to a residue (720mg) which was purified by silica gel chromatography (ethylacetate/dichloromethane, 1:2) to give the title compound (450 mg, 71.0%)as a white powder.

M.S.: m/z 469 (M⁺+1, 100%).

EXAMPLE C 4-fluoro-3-pyridyl-carboxyl-(1R, 3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylMethyl Amide

To a solution of the compound from preparation t (2.0 g, 5.4 mmol) inTHF (120 ml) was added triphenylphosphine (10.5 g, 40 mmol) and water(25 ml). The mixture was stirred under nitrogen at room temperatureovernight. To the reaction mixture was added 15% aqueous HCl (15 ml) andthe mixture was stirred for 30 minutes. The mixture was then poured intowater (200 ml) and washed with ethyl acetate/MTBE (150 ml/50 ml). Someproduct precipitated and was suspended in the aqueous layer. The organiclayer was separated and washed with water (70 ml). The combined aqueousphases (about 270 ml) were washed again with ethyl acetate/MTBE (100ml/50 ml). To the aqueous suspension was added THF (270 ml), K₂CO₃ (41g, 0.3 mol) and 2-fluoropyridine-4-carboxyl chloride (6.4 g, 40 mmol) atroom temperature. After the addition, the reaction mixture was stirredfor 20 hours. The mixture was extracted with ethyl acetate (250 ml×2)and the combined organic extracts were washed with brine (200 ml), anddried over MgSO₄. After filtration, the filtrate was concentrated togive (16.5 g, 99.7%) of a white powder. The product was further purifiedby recrystallization from methanol to afford the title compound (14.0 g,85%).

M.S.: m/e 469 (M⁺+1).

EXAMPLE DN-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-nicotinamide

To a solution of (1R, 3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl amide (700 mg, 2.0 mmol) in 35 mL of dichloromethane was added440 mg (2.4 mmol) of nicotinoyl chloride hydrochloride, 0.85 mL (6.0mmol) of triethylamine and 5 mg of 4-dimethylaminopyridine. The reactionmixture was stirred overnight at ambient temperature, then washed with 1N hydrochloric acid. The aqueous layer was extracted with 20%isopropanol/chloroform. The combined organics were washed with saturatedsodium carbonate, brine, dried over sodium sulfate, filtered andconcentrated to dryness. The residue was chromatographed on silica gelusing methanol/chloroform as eluent to yield 740 mg (82%) of the desiredisomer as a white solid. MS (ion spray) 451.1 (M+1).

EXAMPLE E6-Chloro-N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-nicotinamide

To a solution of5-[3-(aminomethyl)cyclohexyl]-9-chloro-3-methyl-5-hydroisoxazolo[4,3-c]quinolin4-oneHCl (86 mg, 0.22 mmol) in 20 mL of N,N-dimethylformamide was added 62 μL(0.45 mmol) of triethylamine, 43 mg (0.27 mmol) of 6-chloronicotinicacid, 36 mg (0.27 mmol) of 1-hydroxy-7-azabenzo-triazole, 51 mg (0.27mmol) of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochlorideand 5 mg of 4-dimethylaminopyridine. The reaction mixture was stirredovernight at ambient temperature and concentrated to dryness. Theresidue was partitioned between chloroform and saturated sodiumbicarbonate. The mixture was washed with saturated sodium bicarbonate,water, brine, dried over sodium sulfate, filtered and concentrated todryness. The residue was chromatographed on silica gel usingmethanol/chloroform as eluent and concentrated to dryness. The residuewas slurried in ether/hexanes and concentrated to dryness to yield 77 mg(71%) of the desired isomer as a white foam. MS (ion spray) 485.1 (M+).

The compounds of the invention are inhibitors of MRP1. Thus, thecompounds of the invention may be used to inhibit any neoplasm havingintrinsic and/or acquired resistance, conferred in part or in total byMRP1, to an oncolytic or oncolytics. In other words, treatment of such aneoplasm with an effective amount of a compound of this invention willcause the neoplasm to be more sensitive to chemotherapy that wasrendered less efficacious by MRP1.

Camptosar, melphalan, paclitaxel, vinorelbine, mitoxantrone,doxorubicin, daunorubicin, epirubicin, vincristine, and etopsoside areoncolytics that are substrates of MRP1. See Cole, et. al.,“Pharmacological Characterization of Multidrug Resistant MRP-transfectedHuman Tumor Cells”, Cancer Research, 54:5902-5910, 1994. Since MRP1 isubiquitous in mammals, particularly humans, Nooter, K, et. al.,“Expression of the Multidrug Resistance-Associated Protein (MRP) Gene inHuman Cancers”, Clin. Can. Res., 1:1301-1310, (1995), chemotherapy whosegoal is to inhibit a neoplasm employing any of those agents has thepotential to be rendered less efficacious by MRP1. Thus, neoplasms ofthe bladder, bone, breast, lung(small-cell), testis, and thyroid andmore specific types of cancer such as acute lymphoblastic andmyeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue sarcoma,Hodgkin's and non-Hodgkin's lymphomas, and bronchogenic carcinoma may beinhibited with a combination of one or more of the above oncolytics anda compound of this invention.

The biological activity of the compounds of the present invention wasevaluated employing an initial screening assay which rapidly andaccurately measured the activity of the tested compound in inhibitingMRP1 or MDR1. Assays useful for evaluating this reversing capability arewell known in the art. See, e.g., T. McGrath, et al., BiochemicalPharmacology, 38:3611, 1989; D. Marquardt and M. S. Center, CancerResearch, 52:3157, 1992; D. Marquardt, et al., Cancer Research, 50:1426,1990; and Cole, et. al., Cancer Research, 54: 5902-5910, 1994.

Assay for Reversal of MRP1-Mediated Doxorubicin Resistance andMDR1-Mediated Vincristine Resistance

HL60/Adr and HL60/Vinc are continuous cell lines, which were selectedfor doxorubicin and vincristine resistance respectively by culturingHL60, a human acute myeloblastic leukemia cell line, in increasingconcentrations of doxorubicin or vincristine until a highly resistantvariant was attained.

HL60/Adr and HL60/Vinc cells were grown in RPMI 1640 (Gibco) containing10% fetal bovine serum (FBS) and 50 μg/ml GENTAMICIN™ (Sigma). Cellswere harvested; washed twice with assay medium (same as culture media);counted; and diluted to 1×10⁵ cells/ml in assay medium. One hundredmicroliters of cells were aliquoted into wells of a 96 well tissueculture plate. Two columns of each 96 well plate served as a negativecontrol and received assay medium containing no cells.

Test compounds and reference compounds were dissolved in dimethylsulfoxide (DMSO) at a concentration of 5 mM. Samples were diluted inassay medium and 25 μl of each test compound was added to 8 wells. Assaystandards were run in quadruplicate. Assay media was added to half ofthe wells and doxorubicin to the other half of the wells to achieve afinal volume of 150 μl per well.

The plates were incubated at 37° C. for 72 hours in a humidifiedincubator with a 5% carbon dioxide atmosphere. Cell viability andvitality was measured by oxidation of a alamarBlue™ fluorescent dyeusing standard conditions. The plates were incubated for 3 hours at 37°C. Fluorescence was determined using 550 nm excitation and 590 nmemission using a microtitre plate reader.

The ability of a test compound to reverse the resistance of HL60/Adr andHL60/Vinc cells to doxorubicin was determined by comparison of theabsorbance of the wells containing a test compound in addition to theoncolytic (doxorubicin) with the absorbance of wells containing theoncolytic without a test compound. Controls were used to eliminatebackground and to ensure the results were not artifactual. The resultsof the assay are expressed as percent inhibition of cell growth. Theoncolytic alone at the tested concentration minimally inhibits thegrowth of HL60/Adr or HL60/Vinc cells.

Representative compounds of formula I demonstrated a significant effectin reversing the MRP1 multiple drug resistance. Many of the compoundsshowed very significant enhancement of activity in combination with theoncolytic agent as opposed to the oncolytic agent alone. In addition, alarge majority of the compounds tested displayed a significant degree ofselective inhibition of the HL60/Adr cell line over the HL60/Vinc cellline.

When administering an oncolytic in practicing the methods of thisinvention, the amount of oncolytic employed will be variable. It shouldbe understood that the amount of the oncolytic actually administeredwill be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual oncolytic administered, the age, weight,and response of the individual patient (mammal), and the severity of thepatient's symptoms. Of course, the amount of oncolytic administeredshould be decided and closely monitored by that patient's physician.After deciding on the oncolytic or oncolytics to employ, “ThePhysician's Desk Reference®”, published by Medical Economics Company atMontvale, N.J. 07645-1742, is a helpful resource to the physician indeciding on amounts of the oncolytic to administer and is updatedannually.

Preferred formulations, and the methods of this invention employingthose formulations, are those which do not contain an oncolytic. Thus,it is preferred to administer the compounds of this invention separatelyfrom the oncolytic. The oncolytics mentioned in this specification arecommercially available and may be purchased in pre-formulated formssuitable for the methods of this invention.

The compounds of formula I alone, or optionally in combination with anoncolytic, are usually administered in the form of pharmaceuticalformulations. These formulations can be administered by a variety ofroutes including oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, and intranasal. Such formulations are prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound of formula I.

The present invention also includes methods employing pharmaceuticalformulations which contain, as the active ingredient, the compounds offormula I, and optionally an oncolytic, associated with pharmaceuticalcarriers. In making the formulations of the present invention the activeingredient(s) is usually mixed with an excipient, diluted by anexcipient, or enclosed within such a carrier which can be in the form ofa capsule, sachet, paper or other container. When the excipient servesas a diluent, it can be a solid, semi-solid, or liquid material, whichacts as a vehicle, carrier or medium for the active ingredient. Thus,the formulations can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining for example up to 10% by weight of the active compound, softand hard gelatin capsules, suppositories, sterile injectable solutions,and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound(s) to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound(s) is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound(s) is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g., about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Theformulations of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The formulations are preferably formulated in a unit dosage form, eachdosage containing from about 5 to about 100 mg, more usually about 10 toabout 30 mg, of each active ingredient. The term “unit dosage form”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

The compounds of formula I are effective over a wide dosage range. Forexample, dosages per day normally fall within the range of about 0.5 toabout 30 mg/kg of body weight. In the treatment of adult humans, therange of about 1 to about 15 mg/kg/day, in single or divided dose, isespecially preferred. However, it will be understood that the amount ofthe compound actually administered will be determined by a physician, inthe light of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compoundadministered, the age, weight, and response of the individual patient,and the severity of the patient's symptoms, and therefore the abovedosage ranges are not intended to limit the scope of the invention inany way. In some instances dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smallerdoses for administration throughout the day.

For preparing solid formulations such as tablets the principal activeingredient(s) is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient(s) is dispersed evenly throughout the formulation so that theformulation may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The novel formulations which are liquid forms may be incorporated foradministration orally or by injection and include aqueous solutions,suitably flavored syrups, aqueous or oil suspensions, and flavoredemulsions with edible oils such as cottonseed oil, sesame oil, coconutoil, or peanut oil, as well as elixirs and similar pharmaceuticalvehicles.

Formulations for inhalation or insufflation include solutions andsuspensions in pharmaceutical, aqueous or organic solvents, or mixturesthereof, and powders. The liquid or solid formulations may containsuitable pharmaceutical excipients as described supra. Preferably theformulations are administered by the oral or nasal respiratory route forlocal or systemic effect. Compositions in preferably pharmaceuticalsolvents may be nebulized by use of inert gases. Nebulized solutions maybe breathed directly from the nebulizing device or the nebulizing devicemay be attached to a face mask, tent, or intermittent positive pressurebreathing machine. Solution, suspension, or powder formulations may beadministered, preferably orally or nasally, from devices which deliverthe formulation in an appropriate manner.

The following formulation examples are illustrative only and are notintended to limit the scope of the invention in any way. “Activeingredient(s)” means a compound according to formula I or apharmaceutical salt or solvate thereof optionally with one or moreoncolytics.

FORMULATION EXAMPLE 1

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

FORMULATION EXAMPLE 2

A tablet formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

FORMULATION EXAMPLE 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

FORMULATION EXAMPLE 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active ingredient 30.0 mg  Starch 45.0mg  Microcrystalline cellulose 35.0 mg  Polyvinylpyrrolidone 4.0 mg (as10% solution in water) Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1.0 mg Total  120 mg 

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50-60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

FORMULATION EXAMPLE 5

Capsules, each containing 40 mg of medicament are made as follows:

Quantity Ingredient (mg/capsule) Active ingredient  40.0 mg Starch 109.0mg Magnesium stearate  1.0 mg Total 150.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

FORMULATION EXAMPLE 6

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active ingredient 25 mg Saturated fatty acidglycerides to 2,000 mg  

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7

Suspensions, each containing 50 mg of medicament per 5.0 ml dose aremade as follows:

Ingredient Amount Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) 50.0 mg Microcrystalline cellulose (89%)Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 ml

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

FORMULATION EXAMPLE 8

Capsules, each containing 15 mg of medicament, are made as follows:

Quantity Ingredient (mg/capsule) Active ingredient  15.0 mg Starch 407.0mg Magnesium stearate  3.0 mg Total 425.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 425 mg quantities.

FORMULATION EXAMPLE 9

An intravenous formulation may be prepared as follows:

Ingredient Quantity Active ingredient 250.0 mg Isotonic saline 1000 ml

FORMULATION EXAMPLE 10

A topical formulation may be prepared as follows:

Ingredient Quantity Active ingredient 1-10 g Emulsifying Wax 30 g LiquidParaffin 20 g White Soft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

FORMULATION EXAMPLE 11

Sublingual or buccal tablets, each containing 10 mg of activeingredient, may be prepared as follows:

Quantity Ingredient Per Tablet Active ingredient 10.0 mg Glycerol 210.5mg  Water 143.0 mg  Sodium Citrate  4.5 mg Polyvinyl Alcohol 26.5 mgPolyvinylpyrrolidone 15.5 mg Total 410.0 mg 

The glycerol, water, sodium citrate, polyvinyl alcohol, andpolyvinylpyrrolidone are admixed together by continuous stirring andmaintaining the temperature at about 90° C. When the polymers have goneinto solution, the solution is cooled to about 50-55° C. and the activeingredient is slowly admixed. The homogenous mixture is poured intoforms made of an inert material to produce a drug-containing diffusionmatrix having a thickness of about 2-4 mm. This diffusion matrix is thencut to form individual tablets having the appropriate size.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical formulation to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991, which isherein incorporated by reference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonicsolutions, which can transiently open the blood-brain barrier.

We claim:
 1. A compound of formula I:

where: A is a C₃-C₈ cycloalkyl, optionally substituted 1-3 times with aC₁-C₄ alkyl; het is isoxazole; wherein the non-fused carbon atom of theisoxazole may be optionally substituted with R^(b), wherein R^(b) isC₁-C₆ alkyl, optionally substituted aryl, optionally substitutedheterocycle, an amino acid ester, CH₂OH, CH₂O-heterocycle, halo, CH₂N₃,CH₂SR¹, CH₂NR⁴R⁶, OR¹, SR¹³, S(CH₂)_(k)-phenyl, or NR⁴R⁶; k is 0, 1, 2,3, or 4; n is 0, 1,or 2; p is 0 or 1; q is 0, 1, or 2; r is 0, 1,or 2; tis 0, 1, 2, 3, or 4; u is 0, 1, 2, 3, or 4; Y is —EC(O)R³, —E—CH═CHR¹³,—E—C(OH)R¹³, —E—NR⁴R⁵, —E—OR², —E—S(O)_(q)R^(l3), —E—SO₂NR⁴R⁶,—C(R¹¹)═NR⁶, or an optionally substituted heterocycle; E is a bond or—C(R¹¹)(R¹¹)—; R¹ is independently at each occurrence hydrogen or C₁-C₆alkyl; R² is independently at each occurrence hydrogen, C₁-C₆ alkyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted (C₁-C₄alkyl)-aryl, optionally substituted aryl, optionally substitutedheterocycle, C(O)-aryl, C(O)N-phenyl, or (CH₂)₂NR⁴R⁵; R³ isindependently at each occurrence hydrogen, C₁-C₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl,optionally substituted aryl, optionally substituted heterocycle, OR¹³,or NR⁴R⁶; R⁴ is independently at each occurrence hydrogen, C₁-C₆ alkyl,optionally substituted (C₁-C₆ alkyl)-aryl, SO₂CH₃, or optionallysubstituted aryl; or R⁵, R⁶, or R^(6′) combine with R⁴ to form ═CR¹R¹⁴;R⁵ is independently at each occurrence hydrogen, C₁-C₆ alkyl, C₁-C₄alkoxy, optionally substituted heterocycle, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-C₁₀ bicycloalkyl, optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, optionallysubstituted (C₁-C₄ alkyl)-heterocycle, C(O)C(O)R¹³, C(O)R⁷, CH₂R⁷,SO₂R⁸, or a moiety of the formula

or R⁴ and R⁵ together with the nitrogen to which they are attachedcombine to form an optionally substituted N-heterocycle; R⁶ isindependently at each occurrence hydrogen, C₁-C₆ alkyl, C₁-C₄ alkoxy,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀bicycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle, oroptionally substituted heterocycle; or R⁴ and R⁶ together with thenitrogen to which they are attached combine to form an optionallysubstituted N-heterocycle; R^(6′) is independently at each occurrencehydrogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-C₁₀ bicycloalkyl, optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, optionallysubstituted (C₁-C₄ alkyl)-heterocycle, optionally substitutedheterocycle, C₁-C₄ alkyl)-OR¹³: wherein the (C₁-C₄ alkyl) of the C₁-C₄alkyl)-OR¹³ may be optionally substituted from 1 to 2 times with C₁-C₄alkyl, optionally substituted aryl, or optionally substitutedheterocycle; or R⁴ and R^(6′) together with the nitrogen to which theyare attached combine to form an optionally substituted N-heterocycle; R⁷is independently at each occurrence optionally substituted C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₄ alkoxy)-aryl, C₁-C₄ alkoxy)-heterocycle, C₁-C₄alkoxy)-Si(CH₃)₃, optionally substituted (C₃-C₈ cycloalkyl), optionallysubstituted (C₁-C₄ alkyl)-(C₃-C₈ cycloalkyl), optionally substitutedC₁-C₄ alkyl)-aryl, optionally substituted aryl, diphenylmethyl,optionally substituted C₁-C₄ alkyl)-CO-aryl, optionally substitutedCO-aryl, optionally substituted C₁-C₄ alkyl)-heterocycle, 3-oxo-indanyl,fluoren-9-yl substituted with hydroxy, optionally substitutedCH═CH-heterocycle, optionally substituted phenoxy, optionallysubstituted heterocycle, optionally substituted C₁-C₄ alkyl)-phenoxy,(CH₂)_(t)S(O)_(r)R¹, (CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵),(CH₂)_(t)C(R¹²)(R⁹)O(R¹⁷), (CH₂)_(t)C(R¹²)(R⁹)S(R¹⁷), or NR⁴R^(6′); R⁸is independently at each occurrence optionally substituted C₁-C₆ alkyl,optionally substituted aryl, optionally substituted C₁-C₄ alkyl)-aryl,optionally substituted C₁-C₄ alkyl)-heterocycle, or optionallysubstituted heterocycle; R⁹ is independently at each occurrencehydrogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, optionally substituted heterocycle, (CH₂)_(u)-(C₁-C₆alkoxy), optionally substituted (CH₂)_(u)-O-(C₃-C₈ cycloalkyl),optionally substituted (CH₂)_(u)-(C₁C₄ alkoxy)-aryl, optionallysubstituted (CH₂)_(u)-O-aryl, optionally substituted(CH₂)_(u)-O-heterocycle, (C₁-C₄ alkyl)-CO₂-(C₁-C₆ alkyl), optionallysubstituted (C₁-C₄ alkyl)-CO₂-(C₃-C₈ cycloalkyl), optionally substitutedC₁-C₄ alkyl)-CO₂-(C₁-C₄ alkyl)-aryl, optionally substituted (C₁-C₄alkyl)-CO₂-aryl, or optionally substituted (C₁-C₄alkyl)-CO₂-heterocycle; or R⁹ and R¹² combine to form a C₃-C₈cycloalkyl; R¹⁰ is 0 to 4 substituents from the aryl ring independentlyat each occurrence hydrogen, halo, C(O)R³, cyano, optionally substitutedheterocycle, optionally substituted aryl C≡C—R¹, C₁-C₄ alkoxy, (C₁-C₄alkyl)-phenyl, NR¹⁹R²⁰, CH₂OH, C₂CH₂CO₂CH₂CH₃, or C₂-C₆ alkenyl; R¹¹ isindependently at each occurrence hydrogen, C₁-C₆ alkyl, optionallysubstituted heterocycle, optionally substituted (C₁-C₄alkyl)-heterocycle, optionally substituted aryl, or optionallysubstituted (C₁-C₄ alkyl)-aryl; R¹² is independently at each occurrencehydrogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, optionally substituted C₁-C₄ alkyl)-heterocycle oroptionally substituted heterocycle; R¹³ is independently at eachoccurrence hydrogen, optionally substituted C₁-C₆ alkyl, methoxy,hydroxy, optionally substituted C₃-C₈ cycloalkyl, optionally substituted(C₁-C₄ alkyl)-aryl, optionally substituted aryl, CO₂CH₂CO₂CH₂CH₃, oroptionally substituted heterocycle; R¹⁴ is independently at eachoccurrence C₁-C₆ alkyl or optionally substituted (C₁-C₄ alkyl)-aryl; R¹⁵is independently at each occurrence hydrogen, C₁-C₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀bicycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, optionally substituted C₁-C₄ alkyl)-heterocycle,optionally substituted heterocycle, C(O)OR¹³, SO₂R⁸, C(O)R¹⁸, or amoiety of the formula

R¹⁶ is independently at each occurrence hydrogen, optionally substitutedC₁-C₆ alkyl, optionally substituted aryl, optionally substitutedheterocycle, SO₂CH₃ or —COR⁸; or R¹⁶ and R¹⁵ together with the nitrogento which they are attached combine to form an optionally substitutedN-heterocycle; R¹⁷ is independently at each occurrence hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, COR¹⁸, optionally substituted heterocycle, optionallysubstituted (C₁-C₄ alkyl)-heterocycle, optionally substituted C₁-C₆alkoxy, optionally substituted (C₁-C₄ alkoxy)-aryl, optionallysubstituted (C₁-C₄ alkoxy)-heterocycle, (C₁-C₄ alkyl)-N(R¹)(R¹), or anamino acid ester; R¹⁸ is independently at each occurrence hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, optionally substituted heterocycle, C₁-C₄alkyl)-NHCO₂-(C₁-C₄ alkyl), or optionally substituted (C₁-C₄alkyl)-heterocycle; R¹⁹ is independently at each occurrence hydrogen,CO—(C₁-C₄ alkyl), or optionally substituted C₁-C₆ alkyl; R²⁰ isindependently at each occurrence hydrogen, optionally substituted C₁-C₆alkyl, CH₂OH, or CO—(C₁-C₄ alkyl); or a pharmaceutical salt thereof;wherein: optionally substituted C₁-C₄ alkyl and optionally substitutedC₁-C₆ alkyl refers to a C₁-C₄ alkyl or C₁-C₆ alkyl, respectively,unsubstituted or substituted from 1 to 3 times with halo, C₁-C₄ alkanol,NH₂, or hydroxy; optionally substituted C₃-C₈ cycloalkyl refers to aC₃-C₈ cycloalkyl unsubstituted or substituted once with a phenyl,substituted phenyl, hydroxy, or CO₂R¹ group; optionally substituted(C₁-C₄ alkyl)-(C₃-C₈ cycloalkyl) refers to optionally substituted C₃-C₈cycloalkyl linked through an optionally substituted C₁-C₄ alkyl;optionally substituted O—(C₃-C₈ cycloalkyl) refers to an optionallysubstituted C₃-C₈ cycloalkyl linked through an oxygen atom; optionallysubstituted C₆-C₁₀ bicycloalkyl refers to a C₆-C₁₀ bicycloalkylunsubstituted or substituted once with a phenyl, substituted phenyl. orCO₂R¹ group; optionally substituted aryl refers to a phenyl and naphthylgroup, respectively, unsubstituted or substituted from 1 to 5 timesindependently with C₁-C₆ alkyl, halo, hydroxy, trifluoromethyl, phenyl,phenoxy, SO₂R¹, OR¹¹; NR⁴R⁵, SO₂N(R¹³)₂, NH-Pg, C₁-C₆ alkoxy, benzyloxy,C(O)R¹³, C₅-C₇ cycloalkyl, trifluoromethoxy, SR¹, cyano, or nitro;optionally substituted (C₁-C₄ alkyl)-aryl refers to optionallysubstituted aryl linked through an optionally substituted C₁-C₄ alkyl;optionally substituted O-aryl refers to an optionally substituted aryllinked through an oxygen atom; optionally substituted phenoxy refers toa phenoxy group unsubstituted or substituted from 1 to 3 timesindependently with C₁-C₆ alkyl, halo, hydroxy, trifluoromethyl, NR⁴R⁶,SO₂N(R¹³)₂, NH-Pg, C₁-C₆ alkoxy, benzyloxy, C(O)R¹³, C₅-C₇ cycloalkyl,trifluoromethoxy, cyano, or nitro; optionally substituted C₁-C₄alkyl)-phenoxy refers to unsubstituted or substituted phenoxy linkedthrough an optionally substituted C₁-C₄ alkyl; heterocycle is taken tomean stable unsaturated and saturated 3 to 6 membered rings containingfrom 1 to 4 heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur, said rings being optionally benzofused, All of theserings may be substituted with up to three substituents independentlyselected from the group consisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl,cyano, nitro, hydroxy, —S(O)_(m)-(C₁C₄ alkyl) and —S(O)_(m)-phenyl wherem is 0, 1 or 2; optionally substituted heterocycle refers to aheterocyclic ring unsubstituted or substituted 1 or 3 timesindependently with a C₁-C₆ alkyl, halo, benzyl, optionally substitutedphenyl, SR¹, C₁-C₄ alkoxy, CO₂R¹, nitro, cyano, C₁-C₄ alkyl)-cyano,heterocycle. NR¹⁹R²⁰, COR¹², C₁-C₆ alkanol, benzyloxy, phenoxy,trifluoromethyl, Heterocyclic rings may be additionally substituted 1 or2 times with an oxo group; optionally substituted O-heterocycle refersto an optionally substituted heterocycle linked through an oxygen atom;optionally substituted (C₁-C₄ alkyl)-heterocycle refers to optionallysubstituted heterocycle linked through an optionally substituted C₁-C₄alkyl; N-heterocycle refers to a nitrogen containing heterocycle linkedthrough a nitrogen atom; and optionally substituted N-heterocycle refersto a N-heterocycle, optionally substituted 1 or 3 times independentlywith a C₁-C₆ alkyl, halo, benzyl, optionally substituted phenyl, SR¹,C₁-C₄ alkoxy, CO₂R¹, nitro, cyano, (C₁-C₄ alkyl)-cyano, heterocycle,NR¹⁹R²⁰, COR¹², C₁-C₆ alkanol, benzyloxy, phenoxy, trifluoromethyl; andadditionally substituted 1 or 2 times with an oxo group.
 2. The compoundof claim 1 where the isoxazole is


3. The compound of claim 1 where the isoxazole is


4. The compound of any one of claims 1-3 where A is 1,3-cyclohexyl. 5.The compound of claim 4 where n is
 0. 6. The compound of claim 4 where pis 0 or
 1. 7. The compound of claim 4 where Y is E—NR⁴R⁵.
 8. Thecompound of claim 7 where R⁵ is COR⁷.
 9. The compound of claim 8 whereR⁷ is optionally substituted heterocycle.
 10. The compound of claim 8where R⁷ is optionally substituted CO-aryl.
 11. The compound of claim 8where R⁷ is optionally substituted CO-heteroaryl.
 12. The compound ofclaim 8 where R⁷ is (CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵).
 13. The compound ofclaim 4 where R^(b is) C₁-C₆ alkyl.
 14. The compound of claim 13 whereR^(b) is methyl.
 15. The compound of claim 4 where R¹⁰ is halo.
 16. Thecompound of claim 15 where R¹⁰ is chloro.
 17. The compound of claim 16where R¹⁰ is 9-chloro.
 18. The compound of claim 1 selected from thegroup consisting ofN-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-piperidylacetamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(2-chloro(4-pyridyloxy))acetamide,N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}benzamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-hydroxy-2-phenylacetamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-s-yl))cyclohexyl-2(4-fluorophenyl)-2-hydroxyacetamide,N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}-3-pyridylcarboxamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide,andN-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide.19. A method of inhibiting MRP1 in a mammal which comprisesadministering to a mammal in need thereof an amount effective to inhibitMRP1 of a compound of formula I, as defined in claim 1, or apharmaceutical salt thereof.
 20. The method according to claim 19 wherethe mammal is a human.
 21. The method of claim 19 where het is


22. The method of claim 19 where het is


23. The method of any one of claims 19-22 where A is 1,3-cyclohexyl. 24.The method of claim 23 where n is
 0. 25. The method of claim 23 where pis 0 or
 1. 26. The method of claim 23 where Y is E—NR⁴R⁵.
 27. The methodof claim 26 where R⁵ is COR⁷.
 28. The method of claim 27 where R⁷ isoptionally substituted heterocycle.
 29. The method of claim 27 where R⁷is optionally substituted CO-aryl.
 30. The method of claim 27 where R⁷is optionally substituted CO-heteroaryl.
 31. The method of claim 27where R⁷ is (CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵).
 32. The method of claim 23where R^(b) is C₁-C₆ alkyl.
 33. The method of claim 32 where R^(b) ismethyl.
 34. The method of claim 23 where R¹⁰ is halo.
 35. The method ofclaim 34 where R¹⁰ is chloro.
 36. The method of claim 35 where R¹⁰ is9-chloro.
 37. The method of claim 19 wherein the compound is selectedfrom the group consisting ofN-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-piperidylacetamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(2-chloro(4-pyridyloxy))acetamide,N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}benzamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-hydroxy-2-phenylacetamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-fluorophenyl)-2-hydroxyacetamide,N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}-3-pyridylcarboxamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide,andN-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide.38. A pharmaceutical formulation comprising a compound of formula I, asdefined in claim 1, or a pharmaceutical salt thereof; in combinationwith one or more pharmaceutical carriers, diluents, or excipientstherefor.
 39. A pharmaceutical composition for inhibiting MRP1 in amammal which comprises an effective amount of a compound of formula I,as defined in claim 1, or a pharmaceutical salt thereof.